TW202419090A - NLRP3 inflammasome inhibitor and use thereof - Google Patents

Abstract

The present invention belongs to the technical field of medicine, relates to an NLRP3 inflammasome inhibitor and a use thereof, and specifically relates to a compound represented by a general formula (A') or a pharmaceutically acceptable salt, stereoisomer and deuterated product thereof, the definition of each group being as defined in the description. Studies have shown that the compound represented by general formula (A') or the pharmaceutically acceptable salt, stereoisomer and deuterated product thereof have high biological activity against an NLRP3 inflammasome, and have important clinical development value for the treatment of NLRP3-related diseases. Y-W-R3 (A').

Description

NLRP3 inflammasome inhibitors and their applications

The present invention belongs to the field of medical technology, and specifically relates to NLRP3 inflammasome inhibitors and applications thereof.

Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) belongs to the NOD-like receptors (NLRs) family and is also known as "pyrin domain-containing protein 3". NLRP3 contains three modules: pyrin domain (PYD), nucleotide binding site domain (NBD) and leucine-rich repeat sequence (LRR). When stimulated by sterile inflammatory danger signals, NLRP3 interacts with the adaptor protein apoptosis-associated speck-like protein (ASC) and pro-caspase 1 to form the NLRP3 inflammasome. Activation of the NLRP3 inflammasome leads to the release of interleukin-1β (IL-1β) and interleukin-18 (IL-18).

The activation of NLRP3 inflammasome usually requires two steps. The first step involves the initiation of signals, in which Toll-like receptors recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), and then transmit the signal to the cell, mediating the activation of the NF-κB signaling pathway, and then upregulating the transcription levels of NLRP3 inflammasome-related components including inactive NLRP3 and pro-IL-1β. The second step is the activation signal. After receiving signals such as ATP and nigericin, the P2X7 receptor and others cause NLRP3 monomers to oligomerize to form NLRP3 oligomers, and then recruit ASC and pro-caspase 1 to assemble into the NLRP3 inflammasome complex. This triggers the conversion of pro-caspase 1 to caspase 1, as well as the production and secretion of mature IL-1β and IL-18.

Activation of the NLRP3 inflammasome is associated with a variety of diseases. Examples include: autoinflammatory febrile syndromes such as cryopyrin-associated periodic syndrome (CAPS), sickle cell disease, systemic lupus erythematosus (SLE), chronic liver disease, nonalcoholic steatohepatitis (NASH), gout, pseudogout (chondrocalcinosis), type I and type II diabetes and related complications (e.g., nephropathy, retinopathy), neuroinflammatory disorders (e.g., multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Alzheimer's disease), atherosclerosis and cardiovascular risk (e.g., hypertension), hidradenitis purulentis, wound healing and scarring, and cancer (e.g., colorectal cancer, lung cancer, myeloproliferative neoplasms, leukemia, myelodysplastic syndrome (MDS), myelofibrosis). Most treatments involve treating the symptoms, slowing the progression of the disease/disorder, and surgery as a last resort.

WO2020234715A1 discloses a series of NLRP3 inhibitors. This patent discloses for the first time the use of pyridamole-3-ylphenol compounds in the treatment of diseases mediated by NLRP3.

There are relatively few varieties of NLRP3 inflammasome inhibitors under development, and developing NLRP3 inflammasome inhibitors with higher activity and better drugability has become a clinical need.

Problems to be solved by invention

The present invention studies the following compounds or their pharmaceutically acceptable salts, stereoisomers, and deuterated products thereof. The study found that the compounds or their pharmaceutically acceptable salts, stereoisomers, and deuterated products thereof have high biological activity on NLRP3 inflammasomes and have important clinical development value for the treatment of NLRP3-related diseases.

Solutions to solve problems

A compound represented by general formula (A') or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof: (A')

Among them, W is selected from , , or ;

Select from single key or double key;

R ₁ is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, halogenated C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , _{-S 1-6 alkyl} , or absent;

_R2 is independently selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, _C1-6 alkyl, halogenated C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _{C2-6 alkenyl, C2-6 alkynyl} , 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N( _C1-6 alkyl) ₂ , _{-SC1-6 alkyl} , or absent;

R ₁ and R ₂ are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl;

or

_R1 , _R2 and the C or N atom to which they are attached form a 5-12 membered ring A; the 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, oxo, _C1-6 alkyl, -NH- _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylsulfonyl, -N( _C1-6 alkyl) ₂ ; the 5-12 membered ring is selected from 5-12 membered cycloalkyl, 5-7 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-7 membered cycloalkenyl, 6-12 membered condensed cycloalkyl, 5-12 membered heterocyclic group, 5-7 membered heterocyclic group, 6-12 membered condensed heterocyclic group, aryl, 5-12 membered heteroaryl, 8-12 membered condensed heteroaryl, 5-7 membered heteroaryl;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -C _1-6 alkylene-R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, 5-7 membered heteroaryl groups, C _2-6 alkenylcarbonyl, sulfonyl, C _1-6 alkylcarbonyl, ureido C _1-6 alkyl, hydroxyl C _1-6 alkyl, hydrazine, C _1-6 alkylsulfonyl C _1-6 alkyl;

The substituents on _R5 are selected from _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, _C1-6 alkylsulfonyl;

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic, 3-12 membered cycloalkyl;

Said Y is substituted with 1-2 substituents selected from C _2-6 alkenyl, C _2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl;

When the substituent on Y is selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, and sulfonyl, the substituent is optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, and 3-6 membered cycloalkyl;

When the substituent on Y is selected from C _2-6 alkenyl and C _2-6 alkynyl, the substituent is optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl;

When W is selected from When R ₁ and R ₂ do not form a ring with the C to which they are connected.

In any of the above technical solutions,

W Selected from ,

R ₁ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-7 membered heterocyclic group, 4-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, preferably, R ₁ is selected from hydrogen, cyano, halogenated C _1-6 alkyl.

In any of the above technical solutions,

in,

W Selected from ,

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic, 3-12 membered cycloalkyl;

The Y is substituted with a C _2-6 alkynyl group, and may be further optionally substituted with 1-2 substituents selected from the group consisting of halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , and -S _1-6 alkyl;

The substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

The substituents on Y are selected from _C2-6 alkynyl, and the substituents are optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl;

R ₅ is optionally substituted with a substituent selected from hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, hydrazino, ureido C _1-6 alkyl, preferably, R ₅ is substituted with hydroxy C _1-6 alkyl or C _1-6 alkoxy C _1-6 alkyl.

In any of the above technical solutions,

in,

W Selected from ,

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic, 3-12 membered cycloalkyl;

The Y is substituted with a C _2-6 alkenyl group, and may be further optionally substituted with 1-2 substituents selected from the group consisting of halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , and -S _1-6 alkyl;

The substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

The substituents on Y are selected from _C2-6 alkenyl, and the substituents are optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups, 5-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; and R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxyl} , 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, 5-7 membered heteroaryl groups, C _2-6 alkenylcarbonyl, sulfonyl, C _1-6 alkylcarbonyl, ureido C _1-6 alkyl, hydroxyl C _1-6 alkyl, hydrazino, C _1-6 alkylsulfonyl C _1-6 alkyl.

In any of the above technical solutions,

in,

W Selected from ,

At least one of R ₁ and R ₂ is selected from C _2-6 alkenyl, C _2-6 alkynyl, and cyano. Preferably, at least one of R ₁ and R ₂ is selected from C _2-3 alkenyl, C _2-3 alkynyl, and cyano.

_R1 and _R2 are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl.

In any of the above technical solutions,

in,

W Selected from ,

_R1 is selected from hydrogen;

_R2 is selected from hydrogen.

In any of the above technical solutions,

in,

W Selected from ,

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic, 3-12 membered cycloalkyl;

The Y is substituted with a propynyl group, and may be further optionally substituted with 1-2 substituents selected from the group consisting of halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , and -S _1-6 alkyl;

The substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

The substituents on Y are selected from propynyl, and the substituents are optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl;

R ₅ is selected from 3-7 membered cycloalkyl groups, preferably, R ₅ is selected from cyclobutane and cyclohexane.

In any of the above technical solutions,

in,

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is substituted with 1-2 substituents selected from deuterium, deuterated C _1-6 alkyl groups, ethyl groups, cyclopropyl groups, halogen groups, and halogenated C _1-6 alkyl groups. Preferably, said R ₅ is substituted with 1-2 substituents selected from deuterium, deuterated methyl groups, ethyl groups, cyclopropyl groups, and difluoroethane groups.

In any of the above technical solutions,

in,

W Selected from ,

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is substituted by 1-2 substituents selected from hydroxy C _1-6 alkyl groups, preferably, said R ₅ is substituted by hydroxyethyl groups.

In any of the above technical solutions,

in,

Y is selected from aryl groups;

The Y is substituted with 1-2 substituents selected from _C2-6 alkenyl and _C2-6 alkynyl, and may be further substituted with 1-2 substituents selected from hydroxyl, halogen and halogenated _C1-6 alkyl. Preferably, the Y may be further substituted with hydroxyl and halogenated _C1-6 alkyl. Preferably, the Y is substituted with _C2-6 alkynyl and hydroxyl substituents. The _C2-6 alkynyl may be further substituted with halogenated _C1-6 alkyl. Preferably, the Y is substituted with _C2-6 alkynyl, hydroxyl and halogen substituents. More preferably, the Y is substituted with trifluoromethylethynyl and hydroxyl substituents. More preferably, the Y is substituted with substituents selected from acetylene and propynyl, and may be further substituted with hydroxyl and fluorine substituents.

In any of the above technical solutions,

Among them, W is selected from ;

When R ₂ is hydrogen, R ₁ is not selected from methyl and cyclopropyl.

In any of the above technical solutions, R ₅ is optionally substituted by a substituent selected from hydroxyl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, but does not include the following compounds: , .

In any of the above technical solutions,

Among them, W is selected from ;

_R1 is selected from hydrogen, halogen, _C1-6 alkyl, halogenated _C1-6 alkyl, 3-7 membered cycloalkyl;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; said R ₅ is optionally substituted with 1-4 substituents selected from deuterated C _1-6 alkyl groups, C _1-6 alkyl groups, halogenated C _1-6 alkyl groups, 3-7 membered cycloalkyl groups, hydroxy groups, and hydroxy C _1-6 alkyl groups;

Y is selected from aryl groups;

The Y is substituted with a substituent selected from _C2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, 3-7 membered cycloalkyl;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions,

in,

R ₁ and R ₂ are selected from hydrogen, halogen, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, and cyclobutyl;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen or methyl;

_R5 is selected from piperidine, cyclohexyl, cyclopentyl, and cyclobutyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

R ₁ and R ₂ are selected from methyl, trifluoromethyl, difluoromethyl and cyclopropyl;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen;

_R5 is selected from piperidinyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, methyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from fluorine, methyl, cyclopropyl, trifluoromethyl, and difluoromethyl;

The substituents on _R5 are selected from methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, difluoroethane, and hydroxyethyl.

In any of the above technical solutions,

in,

W Selected from ,

R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, -N(C _1-6 alkyl) ₂ or are absent. Preferably, R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, -N(CH ₃ ) ₂ ;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

Y is selected from aryl groups;

The Y is substituted by a C _2-6 alkynyl group, and may be further optionally substituted by 1-2 substituents selected from a hydroxyl group, a C _1-6 alkyl group, a halogenated C _1-6 alkyl group, and a 3-7 membered cycloalkyl group;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

The R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; the R ₅ is optionally substituted by a substituent selected from hydroxy C _1-6 alkyl groups, C _1-6 alkoxy C _1-6 alkyl groups, hydrazino groups, and ureido C _1-6 alkyl groups. Preferably, R ₅ is substituted by hydroxy C _1-6 alkyl groups and C _1-6 alkoxy C _1-6 alkyl groups.

In any of the above technical solutions, formula (A') is not the following compound, , ,

In any of the above technical solutions, when R ₅ is substituted by hydroxyethyl, R ₁ is not methyl.

In any of the above technical solutions, when R ₅ is substituted by hydroxyethyl, R ₁ or R ₂ is selected from cyclopropyl.

in,

W Selected from ,

R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, -N(C _1-6 alkyl) ₂ or are absent;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; said R ₅ is substituted by 1-2 substituents selected from hydroxy C _1-6 alkyl groups;

Y is selected from aryl groups;

The Y is substituted with a substituent selected from _C2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, 3-7 membered cycloalkyl;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions,

in,

W Selected from ,

R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, -N(CH ₃ ) ₂ ;

R ₃ is selected from NR ₄ R ₅ ;

_R4 is selected from hydrogen;

R ₅ is selected from piperidinyl, cyclobutyl, and cyclohexyl; said R ₅ is optionally substituted with 1-4 substituents selected from hydroxyl, C _1-6 alkyl, cyano C _1-6 alkyl, and hydroxyl C _1-6 alkyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

in,

Y is selected from phenyl;

The Y is substituted with 1-2 substituents selected from _C2-6 alkenyl and _C2-6 alkynyl, and may be further substituted with 1-2 substituents selected from hydroxy and halogenated _C1-6 alkyl. Preferably, the Y may be further substituted with hydroxy and halogenated _C1-6 alkyl. Preferably, the Y is substituted with _C2-6 alkynyl and hydroxy substituents. The _C2-6 alkynyl may be further substituted with halogenated _C1-6 alkyl. More preferably, the Y is substituted with trifluoromethylethynyl and hydroxy substituents.

In any of the above technical solutions,

in,

At least one of R ₁ and R ₂ is selected from halogenated C _1-6 alkyl groups. Preferably, at least one of R ₁ and R ₂ is selected from fluorine-substituted C _1-6 alkyl groups. More preferably, at least one of R ₁ and R ₂ is selected from trifluoromethyl groups.

In any of the above technical solutions,

R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, -N(C _1-6 alkyl) ₂ or are absent;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; said R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated C _1-6 alkyl, ethyl, and cyclopropyl groups, preferably, said R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated methyl, ethyl, and cyclopropyl groups;

Y is selected from aryl groups;

The Y is substituted with a substituent selected from _C2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, 3-7 membered cycloalkyl;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions,

R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, -N(CH ₃ ) ₂ ;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen;

R ₅ is selected from piperidinyl, cyclobutyl, cyclohexyl; said R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated C _1-6 alkyl, ethyl, cyclopropyl, preferably, said R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated methyl, ethyl, cyclopropyl;

Y is selected from phenyl;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

Among them, W is selected from ;

_R1 is selected from hydrogen, halogen, _C1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen or methyl;

R ₅ is selected from piperidine, cyclohexyl, cyclopentyl, cyclobutyl; said R ₅ is optionally substituted with 1-3 substituents selected from deuterated C _1-6 alkyl, C _1-6 alkyl, trifluoromethyl, cyclopropyl, hydroxyl, hydroxy C _1-6 alkyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

Among them, W is selected from ;

_R1 is selected from methyl, trifluoromethyl, difluoromethyl, cyclopropyl;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen;

R ₅ is selected from piperidinyl; said R ₅ is optionally substituted by a substituent selected from deuterated methyl, deuterated ethyl, methyl, ethyl, cyclopropyl, hydroxyethyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, methyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted with a substituent selected from fluorine, methyl, cyclopropyl, trifluoromethyl, and difluoromethyl.

In any of the above technical solutions,

W Selected from ,

Select from double keys;

_R1 is selected from _C1-6 alkyl, 3-7 membered cycloalkyl;

R ₂ does not exist;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; said R ₅ is optionally substituted with 1-4 substituents selected from deuterated C _1-6 alkyl groups, ethyl groups, halogenated C _1-6 alkyl groups, 3-7 membered cycloalkyl groups, hydroxy groups, and hydroxy C _1-6 alkyl groups;

Y is selected from aryl groups;

The Y is substituted with a substituent selected from _C2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, 3-7 membered cycloalkyl;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions,

W Selected from ,

Select from double keys;

_R1 is selected from _C1-6 alkyl, cyclopropyl;

R ₂ does not exist;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen or methyl;

R ₅ is selected from piperidine, cyclohexyl, cyclopentyl, cyclobutyl; said R ₅ is optionally substituted with 1-3 substituents selected from deuterated C _1-6 alkyl, ethyl, trifluoromethyl, cyclopropyl, hydroxyl, hydroxy C _1-6 alkyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

W Selected from ,

Select from double keys;

_R1 is selected from methyl and cyclopropyl;

R ₂ does not exist;

R ₃ is selected from -NR ₄ R ₅ ;

_R4 is selected from hydrogen;

R ₅ is selected from piperidinyl; said R ₅ is optionally substituted with a substituent selected from deuterated methyl, deuterated ethyl, ethyl, cyclopropyl, hydroxyethyl;

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, methyl, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted with a substituent selected from fluorine, methyl, cyclopropyl, trifluoromethyl, and difluoromethyl.

In any of the above technical solutions, R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, -N(C _1-6 alkyl) ₂ or are absent.

In any of the above technical solutions, R ₁ and R ₂ are independently selected from hydrogen, cyano, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, -N(CH ₃ ) ₂ .

In any of the above technical solutions, W is selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In any of the above technical solutions, the R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , preferably, the R ₃ is selected from NR ₄ R ₅ .

In any of the above technical solutions, the R ₄ is selected from hydrogen or C _1-6 alkyl, preferably, the R ₄ is selected from hydrogen or methyl, preferably, the R ₄ is selected from hydrogen.

In any of the above technical solutions,

The R ₅ is selected from 3-7 membered heterocyclic groups and 3-7 membered cycloalkyl groups; the R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered heterocyclic groups and hydroxyl C _1-6 alkyl groups;

The substituents on _R5 are optionally substituted with 1 to 3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, _C1-6 alkylsulfonyl.

In any of the above technical solutions, R ₅ is selected from piperidinyl, cyclobutyl, and cyclohexyl; and R ₅ is optionally substituted with 1-4 substituents selected from hydroxyl, C _1-6 alkyl, cyano C _1-6 alkyl, and hydroxyl C _1-6 alkyl.

In any of the above technical solutions, R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; and R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated C _1-6 alkyl groups, ethyl groups, cyclopropyl groups, halogen groups, and halogenated C _1-6 alkyl groups.

In any of the above technical solutions, the R ₅ is selected from piperidinyl, cyclobutyl, and cyclohexyl; and the R ₅ is substituted by 1-2 substituents selected from deuterium, deuterated methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, and difluoroethane.

In any of the above technical solutions, _R3 is selected from , , , , , , , , , , .

In any of the above technical solutions,

Said Y is selected from aryl groups;

The Y is substituted with a substituent selected from _C2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, _C1-6 alkyl, halogen, halogenated _C1-6 alkyl, and 3-7 membered cycloalkyl;

The _C2-6 alkynyl substituent is optionally substituted with a substituent selected from halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions,

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, C _1-6 alkyl, fluorine, chlorine, bromine, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted by substituents selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl and difluoromethyl.

In any of the above technical solutions,

Y is selected from a benzene ring;

The Y is substituted by a substituent selected from ethynyl and propynyl, and may be further optionally substituted by 1-2 substituents selected from hydroxyl, methyl, fluorine, trifluoromethyl, difluoromethyl, and cyclopropyl;

The ethynyl and propynyl substituents are optionally substituted with substituents selected from bromine, fluorine, methyl, cyclopropyl, trifluoromethyl, and difluoromethyl.

In any of the above technical solutions, Y is selected from , , , , , , .

The compound represented by the general formula (A) or its pharmaceutically acceptable salt or stereoisomer: (A)

Among them, W is selected from , or ;

_X1 and _X2 are independently selected from C or N;

R ₁ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C 2-6 alkenyl, C _2-6 alkynyl, _3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl, or is absent;

R ₂ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C 2-6 alkenyl, C _2-6 alkynyl, _3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl, or is absent;

R ₁ and R ₂ are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl;

or

_R1 , _R2 and the C or N atom to which they are attached form a 5-12 membered ring A; the 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, _C1-6 alkyl, -NH- _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylsulfonyl, -N( _C1-6 alkyl) ₂ ; the 5-12 membered ring is selected from 5-12 membered cycloalkyl, 5-7 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-7 membered cycloalkenyl, 6-12 membered condensed cycloalkyl, 5-12 membered heterocyclic group, 5-7 membered heterocyclic group, 6-12 membered condensed heterocyclic group, aryl, 5-12 membered heteroaryl, 8-12 membered condensed heteroaryl, 5-7 membered heteroaryl;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -C _1-6 alkylene-R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, 5-7 membered heteroaryl groups, C _2-6 alkenylcarbonyl groups, sulfonyl groups, and C _1-6 alkylcarbonyl groups;

When R ₅ is replaced,

Substituents on _R5 : _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, _C1-6 alkylsulfonyl;

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic, 3-12 membered cycloalkyl;

(1) When _X1 and _X2 are selected from C,

The Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, sulfonyl;

(2) When W is selected from , Or when any one or both of _X1 and _X2 are selected from N,

The Y is optionally substituted with 1-3 substituents selected from C _2-6 alkenyl, C _2-6 alkynyl, halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl;

When Y is replaced,

Substituents on Y: C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

Substituents on Y: C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl.

In any of the above technical solutions, the general formula after Y, _R3 and W are connected is selected from , , or .

The present invention also provides a compound represented by general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: (I)

in,

_R1 is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

_R2 is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

R ₁ and R ₂ are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl;

or

_R1 , _R2 and the carbon atom to which they are attached form a 5-12 membered ring A; the 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, _C1-6 alkyl, -NH- _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylsulfonyl, -N( _C1-6 alkyl) ₂ ; the 5-12 membered ring is selected from 5-12 membered cycloalkyl, 5-7 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-7 membered cycloalkenyl, 6-12 membered condensed cycloalkyl, 5-12 membered heterocyclic group, 5-7 membered heterocyclic group, 6-12 membered condensed heterocyclic group, aryl, 5-12 membered heteroaryl, 8-12 membered condensed heteroaryl, 5-7 membered heteroaryl;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -C _1-6 alkylene-R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, 5-7 membered heteroaryl groups, C _2-6 alkenylcarbonyl groups, sulfonyl groups, and C _1-6 alkylcarbonyl groups;

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl, wherein Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, sulfonyl;

When R ₅ is replaced,

Substituents on _R5 : _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, _C1-6 alkylsulfonyl;

When Y is replaced,

Substituents on Y: C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

Substituents on Y: C _2-6 alkenyl, C _2-6 alkynyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl.

Furthermore, the present invention provides a compound represented by the general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: (I)

in,

_R1 is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

_R2 is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, _C2-6 alkenyl, _C2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl;

R ₁ and R ₂ are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl;

or

_R1 , _R2 and the carbon atom to which they are attached form a 5-12 membered ring A; the 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, _C1-6 alkyl, -NH- _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, halogenated _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylsulfonyl, -N( _C1-6 alkyl) ₂ ; the 5-12 membered ring is selected from 5-12 membered cycloalkyl, 5-7 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-7 membered cycloalkenyl, 6-12 membered condensed cycloalkyl, 5-12 membered heterocyclic group, 5-7 membered heterocyclic group, 6-12 membered condensed heterocyclic group, aryl, 5-12 membered heteroaryl, 8-12 membered condensed heteroaryl, 5-7 membered heteroaryl;

R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ ;

_R4 is selected from hydrogen or _C1-6 alkyl;

R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; said R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _{1-6 alkyl, C 1-6 alkoxy} , 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, 5-7 membered heteroaryl groups, C _2-6 alkenylcarbonyl groups, sulfonyl groups, and C _1-6 alkylcarbonyl groups;

Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl, wherein Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, sulfonyl;

When R ₅ is replaced,

Substituents on _R5 : _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl;

When Y is replaced,

Substituents on Y: C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl;

Substituents on Y: C _2-6 alkenyl and C _2-6 alkynyl are not substituted.

The present invention also provides the compound or its pharmaceutically acceptable salt, stereoisomer, having a structure shown in general formula (B): (B)

R ₁ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C 2-6 alkenyl, C _2-6 alkynyl, _3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl, or is absent;

R ₂ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C 2-6 alkenyl, C _2-6 alkynyl, _3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -S _1-6 alkyl, or is absent;

R ₁ and R ₂ are each optionally substituted with 1 to 3 substituents selected from hydroxy, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl;

Any one or both of _X1 and _X2 are selected from N;

Y is substituted by hydroxy and optionally substituted by 1-2 substituents selected from _C2-6 alkenyl, _C2-6 alkynyl, halogen, cyano, amino, hydroxy, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, sulfonyl, -N( _C1-6 alkyl) ₂ , _-S1-6 alkyl.

In any of the above technical solutions, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclic group, 3-7 membered cycloalkyl; Y is substituted by _C2-6 alkenyl, _C2-6 alkynyl and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group _{, 3-7 membered cycloalkyl, C1-6 alkylamino, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, aminocarbonyl, C1-6 alkylaminocarbonyl , sulfonyl} ;

When Y is substituted, the substituents on Y are: C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl;

R ₃ is selected from -NH-R ₅ , and R ₅ is a 3-7 membered heterocyclic group substituted with 1-2 substituents selected from C _1-6 alkyl.

In any of the above technical solutions, the compound provided by the present invention or its pharmaceutically acceptable salt, stereoisomer, has a structure shown in general formula (B): (B)

R ₁ , R ₂ and the C or N atom to which they are connected form a 5-8 membered cycloalkyl, a 5-8 membered cycloalkenyl, a 5-8 membered heterocyclic group, a phenyl group, or a 5-8 membered heteroaryl group; the 5-8 membered cycloalkyl, the 5-8 membered cycloalkenyl, the 5-8 membered heterocyclic group, the phenyl group, or the 5-8 membered heteroaryl group are optionally substituted with 1-4 substituents selected from the group consisting of hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylsulfonyl, or -N(C _1-6 alkyl) ₂ ;

Any one or both of _X1 and _X2 are selected from N;

Y is substituted by hydroxy and optionally substituted by 1-2 substituents selected from _C2-6 alkenyl, _C2-6 alkynyl, halogen, cyano, amino, hydroxy, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, sulfonyl, -N( _C1-6 alkyl) ₂ , _-S1-6 alkyl.

In any of the above technical solutions, Ring A is selected from 5-12 membered cycloalkyl, 5-12 membered cycloalkenyl, 5-12 membered heterocyclic group, aryl group, and 5-12 membered heteroaryl group.

In any of the above technical solutions, ring A is selected from 5-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 5-8 membered heterocyclic group, phenyl, and 5-8 membered heteroaryl.

In any of the above technical solutions, Ring A is selected from phenyl, 5-7 membered heteroaryl; Ring A is optionally substituted with 1-4 substituents selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, Ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, N, and 5-6 membered saturated ring.

In any of the above technical schemes, Ring A is optionally substituted with 1-4 substituents selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, Ring A is not substituted.

In any of the above technical schemes, Ring A is substituted with 1-4 substituents selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ .

In any of the above technical schemes, Ring A is substituted with 1-2 substituents selected from cyano, C _1-6 alkoxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylsulfonyl, and -N(C _1-6 alkyl) ₂ .

In any of the above technical embodiments, Ring A is substituted with a substituent selected from cyano, C _1-6 alkoxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylsulfonyl, and -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, ring A is selected from phenyl, 5-6 membered heteroaryl containing 1-2 heteroatoms selected from O, S, and N, and 5-6 membered saturated rings. Ring A is unsubstituted or substituted with a substituent selected from cyano, C _1-6 alkoxy, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkylsulfonyl, and -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, Ring A is selected from , , , , , Ring A is optionally substituted with 1-4 substituents selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, Ring A is selected from , , , , , , , , , , , , , , , , , Ring A is optionally substituted with 1-2 substituents selected from cyano, nitro, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered cycloalkyl, 5-7 membered heteroaryl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ .

In any of the above technical solutions, ring A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In any of the above technical solutions, R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ ; R ₄ is selected from hydrogen or C _1-6 alkyl; R ₅ is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, 5-7 membered heteroaryl group.

In any of the above technical solutions, _R4 is selected from hydrogen.

In any of the above technical solutions, R ₄ is selected from C _1-6 alkyl.

In any of the above technical solutions, _R4 is selected from methyl and ethyl.

In any of the above technical solutions, R ₃ is selected from -NR ₄ R ₅ , -NR ₄ -C _1-6 alkylene-R ₅ , R ₄ is selected from hydrogen, and R ₅ is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl group, aryl group, and 5-7 membered heteroaryl group.

In any of the above technical solutions, R ₃ is selected from -NR ₄ R ₅ , -NR ₄ -C _1-6 alkylene-R ₅ , R ₄ is selected from hydrogen, and R ₅ is selected from 3-7 membered cycloalkyl and 3-7 membered heterocyclic groups; preferably, R ₃ is selected from -NHR ₅ , and R ₅ is selected from 4-6 membered cycloalkyl and 4-6 membered heterocyclic groups.

In any of the above technical solutions, R ₅ is selected from 4-6 membered cycloalkyl, and 4-6 membered heterocyclic group containing one heteroatom selected from O, N, and S.

In any of the above technical solutions, R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _2-6 alkenylcarbonyl, sulfonyl, C _1-6 alkylcarbonyl; when R ₅ is substituted, the substituents on R ₅ : C _1-6 alkyl, halogenated C 1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, _3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C 2-6 alkenylcarbonyl, sulfonyl, C 1-6 alkylcarbonyl; The substituents are substituted by _1-6 membered alkyl or 3-6 membered cycloalkyl.

In any of the above technical solutions, R ₅ is not substituted.

In any of the above technical solutions, _R5 is substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C2-6 alkenylcarbonyl, sulfonyl, _C1-6 alkylcarbonyl;

In any of the above technical solutions, when R ₅ is substituted, the substituents on R ₅ : C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl are not substituted.

In any of the above technical solutions, when R ₅ is substituted, the substituent on R ₅ : C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl is substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl.

In any of the above technical solutions, _R5 is selected from , , , , , , , , , , , , , , , , , , , , , , , .

Preferably, _R5 is selected from , , , , , , , , , , , , , , , , , , , , , , , .

In any of the above technical solutions, Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl, and Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, and sulfonyl.

In any of the above technical solutions, Y is selected from phenyl, 5-7 membered heteroaryl, 3-8 membered heterocyclic group, 3-7 membered cycloalkyl; Y is substituted by _C2-6 alkenyl, _C2-6 alkynyl and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group _{, 3-7 membered cycloalkyl, C1-6 alkylamino, C1-6 alkylcarbonylamino, C1-6 alkylsulfonyl, aminocarbonyl, C1-6 alkylaminocarbonyl , and} sulfonyl.

In any of the above technical solutions, Y is selected from phenyl, 5-8 membered heteroaryl, 3-8 membered heterocyclic, and 3-7 membered cycloalkyl.

In any of the above technical solutions, Y is selected from phenyl and 5-6 membered heteroaryl.

In any of the above technical solutions, Y is selected from phenyl and 5-6 membered heteroaryl containing 1-2 N heteroatoms.

In any of the above technical solutions, Y is substituted by one substituent selected from _C2-6 alkenyl, _C2-6 alkynyl and optionally substituted by one to two substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl.

In any of the above technical solutions, Y is substituted by 1-2 substituents selected from C _2-6 alkenyl and C _2-6 alkynyl.

In any of the above technical solutions, Y is substituted by a substituent selected from C _2-6 alkenyl and C _2-6 alkynyl.

In any of the above technical solutions, Y is optionally substituted by 1-3 groups selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, and 3-7 membered cycloalkyl group.

In any of the above technical solutions, Y is optionally substituted by 1-2 groups selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, and 3-7 membered cycloalkyl group.

In any of the above technical solutions, Y is substituted by 1-2 substituents selected from _C2-6 alkenyl, _C2-6 alkynyl and optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl.

In any of the above technical solutions, Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and Y is optionally substituted by a substituent selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl.

In any of the above technical solutions, Y is substituted by _C2-6 alkenyl, _C2-6 alkynyl and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C1-6 alkylamino, _C1-6 alkylcarbonylamino, _C1-6 alkylsulfonyl, aminocarbonyl, _C1-6 alkylaminocarbonyl, and sulfonyl.

In any of the above technical solutions, when Y is substituted, the substituents on Y are: C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, optionally substituted with 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl.

In any of the above technical solutions, the substituents on Y: C _2-6 alkenyl, C _2-6 alkynyl are substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl.

In any of the above technical solutions, the substituents on Y: C _2-6 alkenyl and C _2-6 alkynyl are not substituted.

In any of the above technical solutions, Y is selected from phenyl, 5-6 membered heteroaryl, and Y is substituted by a substituent selected from _C2-6 alkenyl, _C2-6 alkynyl, and optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl; the _C2-6 alkenyl, _C2-6 alkynyl is substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl.

In any of the above technical solutions, Y is selected from , , , .

In any of the above technical solutions, when Y is substituted, the substituent on Y is selected from: , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

In any of the above technical solutions, it also includes deuterated products formed after hydrogen in the compound structure is substituted with deuterium.

In any of the above technical solutions, it also includes deuterated products formed by deuteration of hydrogen on the optional substituents of Y, W, and _R3 .

In one embodiment of the present invention, the compound represented by the aforementioned formula (A'), its pharmaceutically acceptable salt or stereoisomer, and its deuterated product are shown in Table 1:

Table 1 Serial number Structure Serial number Structure 17 18 19 20 twenty one twenty two twenty three twenty four 27 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240

In one embodiment of the present invention, a pharmaceutical composition is provided, comprising any one of the above-mentioned compounds or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, and a pharmaceutically acceptable carrier.

In one embodiment of the present invention, the pharmaceutical composition may contain one or more pharmaceutical carriers and may be administered to patients or subjects in need of such treatment by oral, parenteral, rectal or transpulmonary administration. When used for oral administration, the pharmaceutical composition may be prepared into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it may also be prepared into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When preparing oral preparations, appropriate fillers, binders, disintegrants, lubricants, etc. may be added. When used for parenteral administration, the pharmaceutical composition may be prepared into injections, including injection solutions, sterile powders for injection, and concentrated solutions for injection. When preparing the injection, conventional methods in the existing pharmaceutical field can be used for production. When preparing the injection, additives may not be added, or appropriate additives may be added according to the properties of the drug. When used for rectal administration, the drug composition can be prepared into suppositories, etc. When used for transpulmonary administration, the drug composition can be prepared into inhalants or sprays, etc.

The present invention also provides the use of the compound represented by the above-mentioned general formula (A') or its pharmaceutically acceptable salt, stereoisomer, deuterated product thereof, or the above-mentioned drug composition in the preparation of drugs for preventing and/or treating diseases related to NLRP3 inflammasome.

The present invention also provides the use of the above-mentioned compound or its pharmaceutically acceptable salt, stereoisomer, deuterated product, or the above-mentioned drug composition in the preparation of drugs for preventing and/or treating inflammasome-related diseases, immune diseases, inflammatory diseases, autoimmune diseases or autoinflammatory diseases.

The "halogen" mentioned in the present invention refers to fluorine, chlorine, bromine and iodine.

The "hydroxyl group" mentioned in the present invention refers to the -OH group.

The "cyano group" mentioned in the present invention refers to a -CN group.

The "amine group" mentioned in the present invention refers to the -NH ₂ group.

The "carboxyl group" mentioned in the present invention refers to the -COOH group.

The "nitro group" mentioned in the present invention refers to the _-NO2 group.

The "oxo group" described in the present invention refers to a =O group.

The "urea group" mentioned in the present invention refers to a _-HNCONH2 group.

The "hydrazino" group mentioned in the present invention refers to a _-NHNH2 group.

The "deuterated C _1-6 alkyl" mentioned in the present invention refers to an alkyl group substituted by one or more deuterium atoms.

The "C _1-6 alkyl" mentioned in the present invention refers to a straight or branched alkyl group derived from a carbon portion containing 1 to 6 carbon atoms by removing a hydrogen atom, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, iso-pentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, iso-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl and 1-methyl-2-methylpropyl.

The "alkylene" in the "C _1-6 alkylene" mentioned in the present invention refers to a divalent group derived from a C _1-6 alkyl group by removing two hydrogen atoms.

The "halogenated C _1-6 alkyl" as used herein refers to a C ₁ -C ₆ alkyl group substituted by one or more halogen groups as defined above. Examples of halogenated C _1-6 alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromoprop-2-yl, 3-bromo-2-fluoropropyl and 1,4,4-trifluorobut-2-yl.

The "C _1-6 alkoxy" mentioned in the present invention refers to a group in which the "C _1-6 alkyl" defined above is connected to the parent molecule through an oxygen atom, that is, a "C _1-6 alkyl-O-" group, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, neopentoxy and n-hexoxy.

The "halogenated C _1-6 alkoxy group" mentioned in the present invention refers to a C ₁ -C ₆ alkoxy group substituted by one or more halogen groups as defined above, examples of which include but are not limited to fluoromethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The "C _2-6 alkenyl" mentioned in the present invention refers to a straight or branched alkenyl derived from an olefinic moiety of 2 to 6 carbon atoms containing at least one carbon-carbon double bond by removing a hydrogen atom, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1,3-butadi-1-enyl, 1-penten-3-yl, 2-penten-1-yl, 3-penten-1-yl, 3-penten-2-yl, 1,3-pentadien-1-yl, 1,4-pentadien-3-yl, 1-hexen-3-yl, 1,4-hexadien-1-yl. Preferably, the "C _2-6 alkenyl" contains one carbon-carbon double bond.

The "C ₂ - ₆ alkynyl" mentioned in the present invention refers to a straight or branched chain alkynyl derived from an alkynyl moiety of 2 to 6 carbon atoms containing at least one carbon-carbon triple bond by removing a hydrogen atom, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. Preferably, the "C ₂ - ₆ alkynyl" contains one carbon-carbon triple bond.

The "C _1-6 alkylamino", "C _1-6 alkylcarbonylamino", "C _1-6 alkylsulfonyl" and "aminocarbonyl" mentioned in the present invention refer to groups formed in the form of C _1-6 alkyl-NH-, C _1-6 alkyl-C(O)-NH-, C _1-6 alkyl-S(O) ₂ - and NH ₂ -C(O)-, respectively.

It can be understood that in the present invention, When R ₁ and R ₂ form a ring with the C or N atom to which they are connected, X ₁ and X ₂ form a double bond or a single bond according to the chemical bonding rules.

The "5-12 membered ring" mentioned in the present invention includes a carbon ring or a heterocyclic ring that may be formed chemically, such as a 5-12 membered cycloalkyl, a 5-7 membered cycloalkyl, a 5-12 membered cycloalkenyl, a 5-7 membered cycloalkenyl, a 6-12 membered condensed cycloalkyl, a 5-12 membered heterocyclic group, a 5-7 membered heterocyclic group, a 6-12 membered condensed heterocyclic group, an aryl, a 5-12 membered heteroaryl, an 8-12 membered condensed heteroaryl, a 5-7 membered heteroaryl, and the like.

The "3-12 member cycloalkyl" of the present invention refers to a monovalent group or (if necessary) a divalent group (e.g., a 5-12 member cycloalkyl) derived from a 3-12 member cycloalkane, which may be a monocyclic, bicyclic, or polycyclic cycloalkyl system. Unless otherwise specified, all monocyclic and fused rings (e.g., 6-12 member fused cycloalkyl) that may be formed include those fused in the form of a cycloalkyl ring, ... Examples of cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclopentane-1,3-diyl, cyclohexane-1,4-diyl, cycloheptane-1,4-diyl, etc. Fused-ring cycloalkyl includes paracycloalkyl, cycloalkyl bridged, and spirocycloalkyl. The cycloalkyl group may be a 6-11-membered cycloalkyl group such as a 7-10-membered cycloalkyl group, and representative examples thereof include but are not limited to bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. The spirocycloalkyl group may be a 7-12-membered spirocycloalkyl group such as a 7-11-membered spirocycloalkyl group, and examples thereof include but are not limited to: , , , , , The bridged cycloalkyl group may be a 6-10 membered bridged cycloalkyl group, such as a 7-10 membered bridged cycloalkyl group, and examples thereof include but are not limited to: , , , , , base.

The "3-7 membered cycloalkyl" mentioned in the present invention refers to a monovalent group or (if necessary) a divalent group derived from a 3-7 membered cycloalkane. The "3-7 membered cycloalkyl" may be a 3-, 4-, 5-, 6-, or 7-membered cycloalkyl. Examples of the 3-7 membered cycloalkyl include cyclopropane, cyclobutane, cyclopentane, and cyclohexane.

The "cycloalkenyl" mentioned in the present invention refers to a group having at least one double bond in the above-mentioned cycloalkyl group. For example, it can be a "3-12-membered cycloalkenyl", that is, it can have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring-forming carbon atoms. Unless otherwise specified, a certain-membered cycloalkenyl includes all possible monocyclic and condensed rings (including condensed in the form of para-, spiro-, and bridged) that may be formed. The cycloalkenyl can be a 3-12-membered cycloalkenyl, a 3-8-membered cycloalkenyl, a 4-6-membered cycloalkenyl, a 7-11-membered spirocycloalkenyl, a 7-11-membered para-cycloalkenyl, a 6-11-membered bridged cycloalkenyl, etc. Examples of the cycloalkenyl group include cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, 1,4-cyclohexadien-1-yl, cycloheptenyl, 1,4-cycloheptadien-1-yl, cyclooctenyl, 1,5-cyclooctadien-1-yl and the like, but are not limited thereto.

The "5-7 membered cycloalkenyl group" mentioned in the present invention refers to a group having at least one double bond in the 5-7 membered cycloalkyl group, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, etc.

The "3-14 membered heterocyclic group" mentioned in the present invention refers to a monovalent group or (if necessary) a divalent group derived from a 3-14 membered heterocycloalkane, i.e., a non-aromatic cyclic group in which at least one of the 3-14 membered ring carbon atoms is replaced by a heteroatom selected from O, S, S(O), S(O) ₂ , C(O), and N, and preferably contains 1 to 3 heteroatoms. "3-14 membered heterocyclic group" (e.g., 5-14 membered heterocyclic group, 5-12 membered heterocyclic group) includes a monocyclic heterocyclic group, a bicyclic heterocyclic group system, or a polycyclic heterocyclic group system, wherein one or more rings may be saturated or partially saturated, but does not include an aromatic ring. Unless otherwise specified, all possible single rings, fused rings (including fused in the form of fused, spiro or bridged rings), saturated and partially saturated rings are included.

The monocyclic heterocyclic group may be a 3-8 membered heterocyclic group such as a 5-7 membered heterocyclic group, a 3-7 membered heterocyclic group, a 4-7 membered heterocyclic group or a 5-6 membered heterocyclic group, a 3-8 membered nitrogen-containing heterocyclic group such as a 4-7 membered nitrogen-containing heterocyclic group or a 5-6 membered nitrogen-containing heterocyclic group, a 3-8 membered saturated heterocyclic group such as a 5-6 membered saturated heterocyclic group, and the like. Examples include, but are not limited to, cycloaziridinyl, cyclooxiranyl, cyclothiiranyl, cycloaziridinyl, cyclobutanyl, cyclothiiranyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,2-thiazolidinyl, 1,3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperonyl, oxolinyl, 1,4-dioxazolyl, 1,4-oxathiocyclohexyl, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2, 4-dihydro-2H-pyrrolyl, 2,3-dihydro-1H-pyrrolyl, 2,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-imidazolyl, 4,5-dihydro-1H-pyrazolyl, 4,5-dihydro-3H-pyrazolyl, 4,5-dihydrothiazolyl, 2,5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4,5-tetrahydropyridinyl, 1,2-isothiazolyl, 1,4-isothiazolyl or 6H-1,3-isothiazolyl.

Fused heterocyclic groups (such as 6-12 membered fused heterocyclic groups) include fused heterocyclic groups, spiro heterocyclic groups and bridged heterocyclic groups, which may be saturated, partially saturated or unsaturated, but not aromatic. Fused heterocyclic groups may be 5-6 membered monocyclic heterocyclic rings fused to a benzene ring, a 5-6 membered monocyclic cycloalkyl group, a 5-6 membered monocyclic cycloalkenyl group, a 5-6 membered monocyclic heterocyclic group or a 5-6 membered monocyclic heteroaryl group.

The heterocyclic group may be a 6-12 membered heterocyclic group such as a 6-11 membered heterocyclic group or a 7-10 membered heterocyclic group, a 6-11 membered saturated heterocyclic group, or a 6-11 membered nitrogen-containing heterocyclic group. Representative examples thereof include but are not limited to: 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.2.0]heptyl, 3,8-diazabicyclo[4.2.0]octyl, 3,7-diazabicyclo[4.2.0]octyl, octahydropyrrole 4-b][1,4]thiophene-2-yl, octahydro-1H-pyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b][1,4]thiophene-2-yl, octahydro-1H-pyrrolo[3,4-c]pyridyl, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, dihydroindol-1-yl, dihydroindol-2-yl, dihydroindol-3-yl, 2,3-dihydrobenzothiophen-2-yl, octahydro-1H-indolyl, octahydrobenzofuran-3-yl.

The spiroheterocyclic group may be a 6-12-membered spiroheterocyclic group such as a 7-12-membered spiroheterocyclic group, a 7-12-membered saturated spiroheterocyclic group, or a 7-12-membered nitrogen-containing spiroheterocyclic group, examples of which include but are not limited to: , , , , , , , , , , , , and .

The bridged heterocyclic group may be a 6-12 membered bridged heterocyclic group, such as a 6-10 membered bridged heterocyclic group (e.g. a 6-10 membered nitrogen-containing bridged heterocyclic group, especially a 7 membered nitrogen-containing bridged heterocyclic group), or a 7-10 membered bridged heterocyclic group, examples of which include but are not limited to: , , , , , , , , , , and .

The "aryl group" mentioned in the present invention refers to a monovalent or, as required, divalent cyclic aromatic group derived from an aromatic carbocyclic hydrocarbon containing 6 to 14 carbon atoms, including benzene, naphthyl, phenanthryl, etc.

The "5-14 membered heteroaryl" mentioned in the present invention refers to an aromatic 5-14 membered cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from O, S, and N. The "5-14 membered heteroaryl" may be a 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered heteroaryl, preferably containing 1-3 heteroatoms, and including the case where the carbon atom and the sulfur atom are replaced by oxygen or nitrogen, for example, the carbon atom is replaced by C(O), and the sulfur atom is replaced by S(O) or S(O) ₂ . Heteroaryl includes single heteroaryl and condensed heteroaryl. Unless otherwise specified, a certain membered heteroaryl includes all possible single rings, condensed rings, all aromatics, and partially aromatics. The monoheteroaryl group may be a 5-7 membered heteroaryl group such as a 5-6 membered heteroaryl group, examples of which include but are not limited to furanyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thienyl, triazolyl and trithionyl.

In some technical schemes, the fused heteroaryl refers to a group formed by a monocyclic heteroaryl ring fused to a phenyl group, a cycloalkenyl group, a heteroaryl group, a cycloalkyl group or a heterocyclic group. In some technical schemes, the fused heteroaryl (such as an 8-14-membered fused heteroaryl) can be an 8-14-membered heteroaryl group such as a 9-10-membered heteroaryl group, examples of which include but are not limited to benzimidazolyl, benzofuranyl, benzothiophenyl, benzodiazolyl, benzothiadiazolyl, benzothiazolyl, azolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, purinyl, quinolinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydro[c][1,2,5]oxadiazolyl and 6,7-dihydro[c][1,2,5]oxadiazol-4(5H)onyl.

The "pharmaceutically acceptable salt" mentioned in the present invention refers to the addition salts and solvates of pharmaceutically acceptable acids and bases. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, sulfurous acid, formic acid, toluenesulfonic acid, methanesulfonic acid, nitric acid, benzoic acid, citric acid, tartaric acid, maleic acid, hydroiodic acid, alkanoic acid (such as acetic acid, HOOC-(CH ₂ ) _n -COOH (where n=0-4)), etc. Such pharmaceutically acceptable salts also include salts of bases such as sodium, potassium, calcium, ammonium, etc. Those skilled in the art know a variety of non-toxic pharmaceutically acceptable addition salts.

All numerical ranges described in the present invention include both end points of the range, all integers within the range, and sub-ranges formed by these integers. For example, "3-7" includes 3, 4, 5, 6, and 7; "1-4" includes 1, 2, 3, and 4; and "1-3" includes 1, 2, and 3.

The term "optionally" or "optionally" means that the subsequently described event may or may not occur, and that the description includes both the event occurring and the event not occurring.

The "stereoisomers" of the compounds described in the present invention refer to isomers produced by different spatial arrangements of atoms in the molecule. When the compound has asymmetric carbon atoms, enantiomers will be produced; when the compound has a carbon-carbon double bond or a ring structure, cis-trans isomers will be produced.

The term "tautomers" refers to different functional group isomers that are in dynamic equilibrium and can quickly transform into each other. It is a special type of functional group isomerism. For example, when ketones or oximes are present, tautomers will be produced. Representative examples include: keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc.

All enantiomers, diastereomers, racemic isomers, cis-trans isomers, tautomers, geometric isomers, epimers and mixtures thereof of the compounds are included within the scope of the present invention.

In the chemical configuration of the compounds of the present invention, the bond " " indicates that the configuration is not specified, that is, if there are chiral isomers in the chemical structure, the bond " " can be " "or" " or both "and" " Two configurations. In the chemical structure of the compound described in the present invention, " ” indicates the point of attachment to the parent molecule.

The term "deuterated" as used herein refers to a compound or group in which one or more hydrogen atoms are replaced by deuterium.

General preparation method of the compound of the present invention

Unless otherwise specified, all raw materials or intermediates in the preparation methods for which the preparation methods are not provided can be purchased or synthesized by methods known in the public literature. Suitable post-treatment methods described in the preparation methods may include one or a combination of the following conventional post-treatment methods, such as: quenching with water, concentration, adjusting the pH value, extraction with a suitable solvent (such as ethyl acetate, dichloromethane), filtration, drying, etc. Suitable purification methods described in the preparation methods may include one or a combination of the following purification methods, such as: silica gel column chromatography, preparative thin layer chromatography, reverse phase preparative chromatography, recrystallization, slurrying, etc.

The compound represented by the general formula (A') having an alkynyl group substituted on Y can be prepared by the route shown in the following reaction formula 1 or reaction formula 2 .

Reaction 1

Reaction 2

in,

W Selected from , or ;

Select from single key or double key;

R ₃ , R ₁ , and R ₂ are as defined above;

Ring _Y1 is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl group, and the substituents on _Y1 are selected from the substituents further substituted by Y as defined above;

PG is selected from a suitable protecting group on O or N (such as methyl, ethoxymethyl, methoxymethyl, benzyl, 4-methoxybenzyl, t-butyl, t-butyloxycarbonyl, benzyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, etc.)

Ra ₁ is selected from H, C _1-6 alkyl, and Ra ₁ can be connected to B and O atoms through carbon atoms to form a 5-7 membered heterocyclic ring.

Halo is a halogen (such as iodine, bromine, and chlorine);

_Ry1 is selected from hydrogen, halogen, _C1-6 alkyl, 3-6 membered cycloalkyl, halogenated _C1-6 alkyl, cyano, amine, carbonyl, _C1-6 alkyl trisubstituted silyl.

The following provides a method for preparing a compound represented by general formula (A") having an alkynyl group substituted on Y from a compound of formula (IM1) as shown in reaction formula 1 :

The compound of formula (IM1) and the compound of formula (IM2) can be used to prepare the compound of formula (IM3) by Suzuki coupling reaction. The compound of formula (IM1) and the compound of formula (IM2) are added to a suitable solvent (such as 1,4-dioxane and water), a suitable catalyst (such as 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride or tetrakis(triphenylphosphine)palladium) is added, and a suitable base (such as sodium bicarbonate, sodium carbonate or potassium carbonate) is added. Under inert gas protection (such as nitrogen), the mixture is heated and stirred at a suitable temperature (such as 90°C to 110°C) for a suitable period of time (such as 1 to 20 hours). After the reaction is completed, the compound of formula (IM3) is separated by a suitable post-treatment and purification method.

The compound of formula (IM3) is dissolved in a suitable solvent (such as methanol), and a suitable base (such as potassium carbonate) and (1-diazo-2-oxopropyl) dimethyl phosphonate are added, and stirred at room temperature for a suitable period of time (such as 1 to 5 hours). After the reaction is completed, the compound of formula (IM4) is isolated by a suitable post-treatment and purification method.

After the compound of formula (IM4) is reacted under appropriate deprotection conditions, it is separated by appropriate post-treatment and purification methods to obtain the compound of formula (A″). For example, when the protecting group PG on the compound of formula (IM4) is ethoxymethyl, the compound of formula (IM4) is added to a suitable solvent (such as dichloromethane), and a suitable amount of acid (such as a solution of hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) is added, and the mixture is heated at an appropriate temperature. The deprotection reaction is completed after reacting at a suitable temperature (such as room temperature) for a suitable time period (such as 5 minutes to 2.5 hours); when the protecting group PG on the formula (IM4) is methyl, the compound of the formula (IM4) is added to a suitable solvent (such as dichloromethane), and a suitable amount of boron tribromide is added at a suitable temperature (such as 0° C.), and the deprotection reaction is completed after reacting at a suitable temperature (such as room temperature) for a suitable time period (such as 17 hours).

When the substituent _Ry1 on the alkynyl group is not hydrogen, the compound represented by the general formula (A‴) can be prepared by the route shown in the following reaction formula 2. The following provides a method for preparing a compound having a substituent on the alkynyl group represented by the general formula (A‴) from a compound of formula (IM4) as shown in reaction formula 2 :

The compound of formula (IM4) can be used to prepare compounds of formula (IM5) with different substitution types by different reaction conditions. For example, the compound of formula (IM4) is subjected to an alkylation reaction with a halogenated alkane (such as iodomethane) in the presence of a base (such as sodium di(trimethylsilyl)amide) to prepare a compound of formula (IM5) containing an alkyl or halogenated alkyl substituted alkynyl group; the compound of formula (IM4) is subjected to a reaction with a halogenating reagent (such as N-bromosuccinimide) in the presence of a suitable catalyst (such as silver nitrate) to prepare a compound of formula (IM5) containing a halogenated alkynyl group; the compound of formula (IM4) is subjected to a reaction with a trifluoromethylating reagent (such as Togni reagent, Umemoto reagent, etc.) in the presence of a suitable catalyst (such as cuprous iodide), a ligand (such as o-phenanthroline) and a base (such as potassium bicarbonate) to prepare a compound of formula (IM5) containing a trifluoromethyl substituted alkynyl group.

The compound of formula (IM1) can be prepared via the route shown in Reaction Scheme 3 .

Reaction 3

in,

Y ₁ , Halo, PG, and Ra ₁ are as defined above.

The following provides a method for preparing a compound of formula (IM1) from a compound of formula (IM1a) as shown in reaction formula 3 :

The compound of formula (IM1a) is dissolved in a suitable solvent (such as dichloromethane), and a suitable protecting group reagent (such as chloromethoxyethane) and a suitable base (such as sodium hydroxide) are added, and stirred at a suitable temperature (such as 0°C to room temperature) for a suitable period of time (such as 2 to 16 hours). After the reaction is completed, the compound of formula (IM1b) is isolated by a suitable post-treatment and purification method.

The compound of formula (IM1b) can be reacted with a suitable boric acid ester (such as pinacol diborate) through Miyaura coupling reaction to prepare the compound of formula (IM1). The compound of formula (IM1b) and pinacol diborate are added to a suitable solvent (such as 1,4-dioxane), a suitable catalyst (such as 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride) is added, and a suitable base (such as potassium acetate) is added. Under inert gas protection (such as nitrogen), the mixture is heated and stirred at a suitable temperature (such as 100°C) for a suitable period of time (such as 20 hours). After the reaction is completed, the compound of formula (IM1) is isolated by a suitable post-treatment and purification method.

The compound of formula (IM1) can be prepared via the route shown in Reaction Scheme 4 or Reaction Scheme 5 .

Reaction 4

Reaction 5

in,

W Selected from , or ;

Select from single key or double key;

Halo, R ₃ , R ₄ , R ₅ , PG are as defined above;

R _5a is selected from the above-defined R ₅ , and R _5a contains O or N which may be protected by a protecting group;

R _5b , R _5c are selected from hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, halogenated C _1-6 alkyl, halogenated C _3-6 cycloalkyl, 3-7 membered heterocyclic group, aryl, 5-7 membered heteroaryl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, C _1-6 alkylsulfonyl;

R _5b and R _5c may be linked to form a 3-7 membered carbon ring or a 3-7 membered heterocyclic ring;

The following provides a method for preparing a compound of formula (IM2) from a compound of formula (IM2a):

For example, as shown in reaction formula 4 , the compound of formula (IM2a) and the compound of formula (IM2b) are added to a suitable solvent (such as 1,4-dioxane, N , N -dimethylacetamide or n-butanol), and a suitable base (such as N , N -diisopropylethylamine) is added, and heated and stirred at a suitable temperature (such as 100°C to 120°C) for a suitable period of time (such as 1 to 72 hours). After the reaction is completed, the compound of formula (IM2) is separated by a suitable post-treatment and purification method.

In some embodiments, the compound of formula (IM2) can be prepared via the route shown in Reaction Scheme 5 ;

For example, the compound of formula (IM2a) and the compound of formula (IM2c) are added to a suitable solvent (such as N , N -dimethylacetamide, toluene or n-butanol), and a suitable base (such as N , N -diisopropylethylamine) is added, and heated and stirred at a suitable temperature (such as 120°C) for a suitable period of time (such as 1 to 72 hours). After the reaction is completed, the compound of formula (IM2d) is separated by a suitable post-treatment and purification method.

The compound of formula (IM2e) can be obtained by applying appropriate deprotection conditions to the compound of formula (IM2d). For example, the compound of formula (IM2d) is dissolved in a suitable solvent (such as dichloromethane), and a suitable amount of acid (such as a 1,4-dioxane solution of hydrogen chloride or trifluoroacetic acid) is added, and the deprotection reaction is completed after reacting at a suitable temperature (such as room temperature) for a suitable period of time (such as 5 minutes to 2.5 hours).

The compound of formula (IM2e) can be prepared by reducing amination reaction or alkylation reaction. For example, the compound (IM2e) is dissolved in a suitable solvent (such as methanol), and the corresponding aldehyde, ketone or its corresponding acetal, ketone is added, and a suitable reducing agent (such as sodium cyanoborohydride) is added, and the reaction can be converted into the corresponding target product at a suitable temperature (such as room temperature). For another example, the compound (IM2e) is dissolved in a suitable solvent (such as dichloromethane), and the corresponding halogenated alkane is added, and the reaction is converted into the corresponding target product under the condition of a suitable base (such as triethylamine or potassium carbonate). After the reaction is completed, the compound of formula (IM2) is separated by a suitable post-treatment and purification method.

When W in the compound of formula (A') is selected from When the compound of formula (IM2d) in the above reaction formula 5 can also be prepared through the route shown in reaction formula 6 .

in,

R ₁ , R ₄ , R _5a , PG, and Halo are as defined above;

Reaction 6

The preparation method is as follows:

The compound of formula (IM2d1) is oxidized to a compound of formula (IM2d2) under the action of an oxidizing agent, selenium dioxide, and then cyclized with S-methylisothiazide urea hydroiodate to generate a compound of formula (IM2d3); the compound of formula (IM2d3) is oxidized with m-chloroperbenzoic acid to generate a methylsulfonyl compound of formula (IM2d4); the compound of formula (IM2d4) is reacted with a compound of formula (IM2c) under suitable alkali conditions (such as N , N -diisopropylethylamine) to generate a compound of formula (IM2d5); the compound of formula (IM2d5) is then reacted with a halogenated reagent (such as N -bromosuccinimide or dibromohydantoin, etc.) to prepare a compound of formula (IM2d).

When W in the compound of formula (A') is selected from When the compound of formula (IM2e) in the above reaction formula 5 can also be prepared by the route shown in reaction formula 7 .

Reaction 7

in,

R ₄ , R _5a , and PG are as defined above; and Halo is bromine.

The preparation method is as follows:

Compound (IM2f) and compound (IM2c) undergo Buchward coupling reaction in the presence of a suitable catalyst (tri(dibenzylideneacetone) dipalladium), a ligand (such as 1,1'-binaphthyl-2,2'-bisdiphenylphosphine) and a base (such as cesium carbonate) to generate compound (IM2g); compound (IM2g) is oxidized in the presence of m-chloroperbenzoic acid to generate compound (IM2h); compound (IM2h) is then reacted with boron tribromide to prepare compound (IM2e).

In some embodiments, the compound of formula (IM4) described in Reaction Scheme 1 and Reaction Scheme 2 can be prepared via the route shown in Reaction Scheme 8 .

Reaction 8

in,

W Selected from , or ;

Select from single key or double key;

Y ₁ , Halo, R ₁ , R ₂ , Ra ₁ , R ₃ , R ₄ , R ₅ , PG, R _5a , R _5b , R _5c are as defined above;

The following provides a method for preparing a compound of formula (IM4) from a compound of formula (IM1):

The compound of formula (IM1) and the compound of formula (IM2d) can be used to prepare the compound of formula (IM4a) by Suzuki coupling reaction. The compound of formula (IM1) and the compound of formula (IM2) are added to a suitable solvent (such as 1,4-dioxane and water), a suitable catalyst (such as 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride or tetrakis(triphenylphosphine)palladium) is added, and a suitable base (such as sodium bicarbonate, sodium carbonate or potassium carbonate) is added. Under inert gas protection (such as nitrogen), the mixture is heated and stirred at a suitable temperature (such as 90°C to 110°C) for a suitable period of time (such as 1 to 20 hours). After the reaction is completed, the compound of formula (IM4a) is separated by a suitable post-treatment and purification method.

The compound of formula (IM4a) is dissolved in a suitable solvent (such as methanol), and a suitable base (such as potassium carbonate) and (1-diazo-2-oxopropyl) dimethyl phosphonate are added, and stirred at room temperature for a suitable time period (such as 1 to 5 hours). After the reaction is completed, the compound of formula (IM4b) is isolated by a suitable post-treatment and purification method.

The compound of formula (IM4b) is reacted under appropriate deprotection conditions (such as a solution of hydrogen chloride in 1,4-dioxane or trifluoroacetic acid), and then separated by appropriate post-treatment and purification methods to obtain a compound of formula (IM4c).

The compound of formula (IM4) can be prepared by subjecting the compound of formula (IM4c) to a reduction amination reaction or an alkylation reaction. For example, the compound of formula (IM4c) is dissolved in a suitable solvent (such as methanol), and the corresponding aldehyde, ketone or its corresponding acetal, ketal is added, and a suitable reducing agent (such as sodium cyanoborohydride) is added, and the compound is reacted at a suitable temperature (such as room temperature) to be converted into the corresponding target product. For another example, the compound of formula (IM4c) is dissolved in a suitable solvent (such as dichloromethane), and the corresponding halogenated alkane is added, and the compound is reacted in the presence of a suitable base (such as triethylamine or potassium carbonate) to be converted into the corresponding target product. After the reaction is completed, the compound of formula (IM4) can be obtained by separation by suitable post-treatment and purification methods.

When the substituent _Ry1 on the alkynyl group is not hydrogen, the compound of formula (IM5) shown in Reaction Scheme 2 can be prepared via the route shown in Reaction Scheme 9 below.

Reaction 9

in,

W Selected from , or ;

Select from single key or double key;

Y ₁ , R ₁ , R ₂ , R ₃ , R ₄ , PG, R _5a , R _5b , R _5c , Halo are as defined above;

Ry ₁ is as defined above, Ry ₁ is not hydrogen;

The following provides a method for preparing a compound of formula (IM5) from a compound of formula (IM4b) as shown in reaction formula 9 :

The compound of formula (IM4b) can be used to prepare the compound of formula (IM5a) with different substitution types on the alkynyl group through different reaction conditions described in the first step of reaction formula 2 ; the compound of formula (IM5a) can be reacted under appropriate deprotection conditions (such as a solution of hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) to obtain the compound of formula (IM5b); the compound of formula (IM5b) can be used to prepare the compound of formula (IM5) through a reductive amination reaction or an alkylation reaction.

In some embodiments, the compound of formula (IM5) can be prepared via the route shown in Reaction Scheme 10 .

Reaction 10

Wherein, Y ₁ , Halo, W, Ry ₁ , Ra ₁ , R, PG are as defined above;

The following provides a method for preparing a compound of formula (IM5) from a compound of formula (IM5c) as shown in reaction formula 10 :

Under nitrogen protection, the compound of formula (IM5c) and the compound of formula (IM5d) are reacted in the presence of a suitable palladium catalyst (such as bis(triphenylphosphine)palladium dichloride), a copper catalyst (such as cuprous iodide) and a base (such as N , N -diisopropylethylamine) to produce a compound of formula (IM5e) by a Sonogashira cross-coupling reaction; the compound of formula (IM5e) can be reacted with a suitable borate ester (such as diboric acid pinacol ester) through a Miyaura coupling reaction to produce a compound of formula (IM5f); the compound of formula (IM5e) can also be reacted with an organic lithium reagent (such as n-butyl lithium) for a lithiation reaction, and then reacted with a suitable borate ester (such as isopropyl alcohol pinacol borate) to produce a compound of formula (IM5f); the compound of formula (IM5f) and the compound of formula (IM2) can be reacted with the Suzuki reaction described in reaction formula 1 to produce a compound of formula (IM5).

In some embodiments, the compound of formula (IM5a) in Reaction Scheme 9 can be prepared by the reaction shown in the following Reaction Scheme 11 .

Reaction 11

wherein Ry ₁ , Y ₁ , Ra ₁ , R ₄ , W, PG, R _5a , Halo are as defined above;

The compound of formula (IM5a) can be prepared by reacting the compound of formula (IM5e) with the compound of formula (IM2d) through the aforementioned Suzuki reaction.

When W in the compound represented by the general formula (A') is selected from When the compound of formula (A') is used, the compound of formula (A') can be prepared by reaction formula 12 .

Reaction 12

wherein Y ₁ , R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , PG, R _5a , R _5b , R _5c , Halo and Ry ₁ are the same as defined above;

The following provides a method for preparing a compound of formula (A') from a compound of formula (IM8a) via the route shown in reaction formula 12 :

The compound of formula (IM8a) reacts with sulfonic acid chloride or oxalyl chloride to generate the corresponding acyl chloride, which then reacts with the corresponding amine to generate the compound of formula (IM8b); the compound of formula (IM8b) reacts with a sulfiding reagent (such as Lawson's reagent) to generate the compound of formula (IM8c); the compound of formula (IM8c) reacts with methyl iodide to generate the compound of formula (IM8d); the compound of formula (IM8d) reacts with hydrazine hydrate to generate the compound of formula (IM8e); the compound of formula (IM8e) reacts with ethyl thiooxamate under the action of triethylamine to generate the compound of formula (IM8f); the compound of formula (IM8f) reacts with tert-butyl nitrite under the catalysis of a copper salt (such as cuprous bromide, cuprous chloride) to generate the compound of formula (IM8g) by Sandmeyer reaction; the compound of formula (IM8g) reacts with the compound of formula (IM2c) in the presence of a suitable base (such as N , N -diisopropylethylamine) to generate a compound of formula (IM8h); the compound of formula (IM8h) and the compound of formula (IM5d) are reacted in the presence of a suitable palladium catalyst (such as bis(triphenylphosphine)palladium dichloride), a copper catalyst (such as cuprous iodide) and an alkali (such as N , N -diisopropylethylamine) to produce a compound of formula (IM8i); the compound of formula (IM8i) is reacted under suitable deprotection conditions (such as a solution of hydrogen chloride in 1,4-dioxane or trifluoroacetic acid) to obtain a compound of formula (IM8j); the compound of formula (IM8j) is subjected to a reductive amination reaction or an alkylation reaction to produce a compound of formula (IM8); the compound of formula (IM8) is deprotected under suitable deprotection conditions (such as boron tribromide/dichloromethane) to obtain a compound of formula (A').

In some embodiments, the compound of formula (IM8) can also be prepared by the route shown in reaction formula 13:

Reaction 13

Wherein, Y ₁ , R ₁ , R ₄ , R ₅ , PG, Halo, and Ry ₁ are the same as defined above;

The compound of formula (IM8g) reacts with the compound of formula (IM2b) in the presence of a suitable alkali (such as N , N -diisopropylethylamine) to generate the compound of formula (IM8k); the compound of formula (IM8k) and the compound of formula (IM5d) react in the presence of a suitable palladium catalyst (such as bis(triphenylphosphine)palladium dichloride), a copper catalyst (such as cuprous iodide) and an alkali (such as N , N -diisopropylethylamine) to undergo a Sonogashira cross-coupling reaction to prepare the compound of formula (IM8).

When the substituent on Y in the compound represented by general formula (A') is selected from olefins, the compound represented by general formula (A') can be prepared via the route shown in reaction formula 14 or reaction formula 15 .

Reaction 14

Reaction 15

in,

Y ₁ , Y, W, Ry ₁ , R ₃ , PG are as defined above;

Ry ₂ is selected from the group defined by Ry ₁ ;

The compound of formula (IM3) can be reacted with a corresponding phosphine ylide reagent to generate a compound of formula (IM6), and then subjected to the aforementioned appropriate deprotection conditions to generate a compound of formula (A-A′);

Alternatively, the compound of formula (IM5) is subjected to appropriate deprotection conditions to generate the compound of formula (IM7), and the compound of formula (IM7) is subjected to reduction reaction with hydrogen in the presence of Lindlar palladium catalyst to obtain the compound of formula (A-A″).

The compound of formula (IM6) shown in reaction formula 15 can also be prepared by the route shown in reaction formula 16.

Reaction 16

in,

Y ₁ , W, Ry ₁ , Ry ₂ , R ₃ , Ra ₁ , PG, Halo are as defined above;

The following provides a method for preparing a compound of formula (IM6) from a compound of formula (IM1d):

The compound of formula (IM1d) undergoes Wittig reaction with the corresponding phosphine ylide reagent to generate the compound of formula (IM6a), which is then reacted with a suitable boric acid ester (such as pinacol diborate) through the aforementioned Miyaura coupling reaction to obtain the compound of formula (IM6b). The compound of formula (IM6b) and the compound of formula (IM2) undergo the aforementioned Suzuki coupling reaction to generate the compound of formula (IM6);

In some embodiments, the compound of formula (IM6) can also be prepared via the route shown in Reaction Scheme 17 .

Reaction 17

in,

Y ₁ , W, Ry ₁ , Ry ₂ , R ₃ , Ra ₁ , R _5a , R _5b , R _5c , PG, and Halo are as defined above;

The following provides a method for preparing a compound of formula (IM6) from a compound of formula (IM6b):

The compound of formula (IM6b) and the compound of formula (IM2d) are subjected to the aforementioned Suzuki coupling reaction to generate the compound of formula (IM6c); the compound of formula (IM6c) is subjected to the aforementioned appropriate deprotection conditions to generate the compound of formula (IM6d); the compound of formula (IM6d) is then subjected to a reductive amination or alkylation reaction with an aldehyde, a ketone or a halogenated alkane to obtain the compound of formula (IM6).

Effect of invention

The compounds provided by the present invention or their pharmaceutically acceptable salts, stereoisomers, and deuterated products thereof have good inhibitory activity on NLRP3 inflammasomes. At the same time, the compounds of the present invention have obvious advantages in various aspects such as liver microsomes, PK, brain clearance, and safety. Therefore, the compounds of the present invention can be safely and effectively used to prevent and/or treat diseases related to NLRP3 inflammasomes.

In order to make the purpose, technical solution, and advantages of the present invention more clearly understood, the present invention is further described in detail below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative labor are within the scope of protection of the present invention.

The abbreviations and English expressions used in this invention have the following meanings:

"THF" refers to tetrahydrofuran; "DMF" refers to N , N -dimethylformamide; "MeOH" refers to methanol; "EA" refers to ethyl acetate; "DCM" refers to dichloromethane; "DMA" refers to N , N -dimethylacetamide; "MTBE" refers to methyl tert-butyl ether; "EtOH" refers to ethanol; "DMAC" refers to dimethylacetamide; "PE" refers to petroleum ether; "n-BuLi" refers to n-butyl lithium;

“FBS” refers to fetal bovine serum; “PBS” refers to phosphate-buffered saline; “PMA” refers to phorbol myristate; “LPS” refers to lipopolysaccharide; and “Nigericin” refers to nigericin.

Embodiment

The embodiments of the present invention will be described in detail below in conjunction with the embodiments, but those skilled in the art will understand that the following embodiments are only used to illustrate the present invention and should not be considered to limit the scope of the present invention. If no specific conditions are specified in the embodiments, the experiment is carried out according to conventional conditions or conditions recommended by the manufacturer. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially.

Example 1: Synthesis of ( R )-3-(4- ethyl -2- hydroxyphenyl )-4 - methyl -6-((1- methylpiperidin -3- yl ) amino )-1,2,4 -trioxan - 5( 4H )-one (Compound 23 )

Step 1: Synthesis of 4-bromo-2-methoxy- N -methylbenzamide

A solution of 4-bromo-2-methoxybenzyl chloride (32.4 g, 129.85 mmol, 1.0 eq) in dichloromethane (200 mL) was added dropwise to a methylamine aqueous solution (100 mL) and reacted at room temperature for 10 min. The reaction was complete as determined by TLC. The reaction solution was poured into water (100 mL) and extracted with dichloromethane (100 mL×2). The organic phase was dried and concentrated to obtain the product (30 g, yield: 94.6%).

Step 2: Synthesis of 4-bromo-2-methoxy- N -methylthiobenzamide

4-Bromo-2-methoxy- N -methylbenzamide (30 g, 122.90 mmol, 1.0 eq) and Lawson reagent (34.8 g, 86.03 mmol, 0.7 eq) were dissolved in THF (300 mL) and reacted at 70°C for 1 h. The reaction was complete as determined by TLC. The reaction solution was poured into water (300 mL) and extracted with ethyl acetate (300 mL×3). The organic phase was dried and concentrated to obtain the product (31.97 g, yield: 100%).

Step 3: Synthesis of methyl 4-bromo-2-methoxy- N -methylthiobenzoylimidate

4-Bromo-2-methoxy- N -methylthiobenzamide (31.94 g, 122.90 mmol, 1.0 eq) and iodomethane (26.17 g, 184.35 mmol, 1.5 eq) were dissolved in THF (300 mL) and reacted at room temperature for 19 h. TLC detected that the reaction was complete, and the reaction solution was poured into water (500 mL), and the pH value was adjusted to about 8 with sodium bicarbonate, and extracted with ethyl acetate (300 mL×2). The organic phase was dried and concentrated to obtain the product (33.7 g, yield: 100%).

Step 4: Synthesis of N -amino-4-bromo-2-methoxy- N' -methylbenzamidine

Dissolve 4-bromo-2-methoxy- N -methylthiobenzoylimidate (33.7 g, 122.90 mmol, 1.0 eq) and hydrazine hydrate (7.24 g, 122.90 mmol, 1.0 eq) in EtOH (300 mL) and react at 80°C for 0.5 h. The reaction was complete as monitored by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain a crude product (31.7 g, yield: 100%).

Step 5: Synthesis of 6-amino-3-(4-bromo-2-methoxyphenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one

N -amino-4-bromo-2-methoxy- N' -methylbenzamidine (31.7g, 122.90mmol, 1.0eq), ethyl thioxamate (16.37g, 122.90mmol, 1.0eq) and triethylamine (12.44g, 122.90mmol, 1.0eq) were dissolved in EtOH (300 mL) and reacted at 70°C for 16 h. The reaction was complete as monitored by LC-MS. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The crude product was first purified by silica gel column chromatography (methanol: dichloromethane = 1:100), then slurried with ethyl acetate (100mL), and filtered to obtain the product (15.5g, yield: 40.6%).

Step 6: Synthesis of 3-(4-bromo-2-methoxyphenyl)-6-chloro-4-methyl-1,2,4-triazine-5( 4H )-one

Disperse 6-amino-3-(4-bromo-2-methoxyphenyl)-4-methyl-1,2,4-trioxan-5(4 H )-one (5.0 g, 16.07 mmol, 1.0 eq) and CuCl (3.18 g, 32.14 mmol, 2.0 eq) in acetonitrile (50 mL), react at 70°C for 5 min under nitrogen protection, slowly add tert-butyl nitrite (3.31 g, 32.14 mmol, 2.0 eq) dropwise, and react at 70°C for 2 h. The reaction was complete as monitored by TLC, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: dichloromethane = 1:5) to obtain the product (1.5 g, yield: 28.2%).

Step 7: Synthesis of (R )-3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3-(4-Bromo-2-methoxyphenyl)-6-chloro-4-methyl-1,2,4-trioxan-5( 4H )-one (1.5 g, 4.54 mmol, 1.0 eq), ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.09 g, 5.45 mmol, 1.2 eq) and N , N -diisopropylethylamine (880 mg, 6.81 mmol, 1.5 eq) were dissolved in 1,4-dioxane (30 mL) and reacted at 100℃ for 18 h. LC-MS detected that the reaction was complete. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:100) to obtain the product (1.2 g, yield: 53.6 %).

Step 8: Synthesis of (R )-3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxo-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.21 mmol, 1.0 eq), _PdCl2 ( _PPh3 ) ₂ (84 mg, 0.12 mmol, 0.1 eq) and CuI (68 mg, 0.36 mmol, 0.3 eq) were added to diisopropylamine (20 mL) and reacted at 60℃ for 10 min under nitrogen protection. Trimethylsilylene (1.19 g, 12.10 mmol, 10 eq) was added and reacted at 60℃ for 5 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (methanol: dichloromethane = 1:100) to obtain the product (500 mg, yield: 80.8 %).

Step 9: Synthesis of (R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.98 mmol, 1.0 eq.) in dichloromethane (10 mL), cool to -70°C, add boron tribromide (736 mg, 2.94 mmol, 3.0 eq), warm to room temperature naturally, and react for 17 h. The reaction was complete as determined by LC-MS. An appropriate amount of methanol was added to the reaction solution for quenching. The reaction solution was poured into water (20 mL) and extracted with methanol/dichloromethane (1:10, 30 mL×6). The organic phase was dried and concentrated to obtain a crude product (200 mg, yield: 62.9%).

Step 10: Synthesis of (R )-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-trioxan-5( 4H )-one

( R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (200 mg, 0.61 mmol, 1.0 eq) and formaldehyde aqueous solution (37%) (50 mg, 0.61 mmol, 1.0 eq) were dissolved in methanol (30 mL) and stirred at room temperature for 10 min. Sodium cyanoborohydride (38 mg, 0.61 mmol, 1.0 eq) was added and reacted at room temperature for 10 min. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (10 mL) and extracted with dichloromethane (20 mL×4). The organic phase was dried, concentrated, and purified by preparative thin layer chromatography (dichloromethane: methanol = 7:1) to obtain the product (55 mg, yield: 26.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.46(s, 1H), 7.32-7.30 (d, 1H), 7.05-7.03 (d, 2H), 6.89 (s, 1H), 4.29 (s, 1H), 4.05 (s, 1H), 3.18 (s, 3H), 2.81 (s, 1H), 2.27 (s, 5H), 1.71-1.56 (d, 5H).

Molecular formula: C ₁₈ H ₂₁ N ₅ O ₂ Exact molecular weight: 339.17 LC-MS (Pos, m/z ) = 340.15 [M+H] ⁺ .

Example 2: Synthesis of ( R )-3-(2- hydroxy -4-( prop -1- yn -1- yl ) phenyl )-4 - methyl -6-((1- methylpiperidin -3- yl ) amino )-1,2,4 -trioxan - 5( 4H )-one (Compound 27 )

Step 1: Synthesis of (R )-3-((3-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Dissolve ( R )-3-((3-(4-bromo-2-methoxyphenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxo-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.6 g, 1.21 mmol, 1.0 eq), _PdCl2 ( _PPh3 ) ₂ (84 mg, 0.12 mmol, 0.1 eq) and CuI (68 mg, 0.36 mmol, 0.3 eq) in diisopropylamine (10 mL) and react at 60℃ for 10 min under nitrogen protection. Add propyne tetrahydrofuran solution (1 mol/L, 12.1 mL, 10 eq) and react at 60℃ for 16 h. LC-MS detected the presence of the target product. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phase was dried and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate: PE = 1:1) to obtain the product (300 mg, yield: 54.6 %).

Step 2: Synthesis of (R )-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

( R )-3-((3-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxo-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (0.3 g, 0.66 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL), cooled to -70°C, and added with boron tribromide (496 mg, 1.98 mmol, 3.0 eq) and reacted for 3 h. LC-MS detected that the reaction was complete, and an appropriate amount of methanol was added to the reaction solution to quench. The reaction solution was poured into water (20 mL), extracted with dichloromethane (10 mL×4), and the organic phase was dried and concentrated to obtain a crude product (100 mg, yield: 44.6%).

Step 3: Synthesis of (R )-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-trioxan-5( 4H )-one

( R )-3-(2-Hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (100 mg, 0.29 mmol, 1.0 eq) and 37% formaldehyde aqueous solution (24 mg, 0.29 mmol, 1.0 eq) were dissolved in methanol (3 mL) and stirred at room temperature for 5 min. Sodium cyanoborohydride (18 mg, 0.29 mmol, 1.0 eq.) was added and reacted at room temperature for 5 min. The reaction was complete as monitored by TLC. The reaction solution was poured into water (10 mL) and extracted with dichloromethane (20 mL×3). The organic phase was dried and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 8:1) to obtain the product (10 mg, yield: 9.8%).

¹ H NMR (400 MHz, CDCl ₃ ) δ(ppm): 7.23-7.21 (d, 1H), 7.12 (s, 1H), 6.99-6.97 (d, 1H), 6.48 (s, 1H), 4.25 (s, 1H), 3.57 (s, 3H), 2.58 (s, 2H), 2.33 (s, 4H), 2.09 (s, 3H), 1.75-1.69 (d, 5H).

Molecular formula: C ₁₉ H ₂₃ N ₅ O ₂ Exact molecular weight: 353.19 LC-MS (Pos, m/z ) = 354.07 [M+H] ⁺ .

Example 3: Synthesis of ( R )-3-(2- hydroxy -4-( prop -1- yn -1- yl ) phenyl )-6-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino )-4- methyl -1,2,4 -trioxan - 5( 4H )-one (Compound 33 )

Step 1: Synthesis of (R )-3-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-trioxan-5( 4H )-one

( R )-3-(2-Hydroxy-4-(prop-1-yn-1-yl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (150 mg, 0.44 mmol, 1.0 eq), bromoethanol (165 mg, 1.32 mmol, 3.0 eq) and TEA (233 mg, 2.20 mmol, 5.0 eq) were dissolved in THF (5 mL) and reacted at 60°C for 3 h. The reaction was complete as monitored by LC-MS. The reaction solution was poured into water (20 mL) and extracted with DCM (20 mL×3). The organic phase was dried, concentrated, and purified by preparative thin layer chromatography (DCM:MeOH=8:1) to obtain the product (80 mg, yield: 47.6%).

¹ H NMR (400 MHz, CD ₃ OD) δ(ppm): 7.29-7.27 (d, 1H), 7.00-7.98 (d, 1H), 6.95 (s, 1H), 4.25-4.21 (m, 1H), 3.79-3.76 (t, 2H), 3.34 (s, 3H), 3.28 (s, 1H), 2.97 (s, 1H), 2.84-2.83 (d, 2H), 2.66-2.61 (t, 2H), 2.06 (s, 3H), 1.97-1.95 (d, 1H), 1.93-1.90 (t, 1H), 1.83-1.78 (m, 1H), 1.77-1.68 (m, 1H).

Molecular formula: C ₂₀ H ₂₅ N ₅ O _3Exact molecular weight: 383.20 LC-MS (Pos, m/z ) = 384.22 [M+H] ⁺ .

Example 4: Synthesis of ( R )-3-(4- ethynyl -2- hydroxyphenyl )-6-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino )-4- methyl -1,2,4 -trioxan - 5( 4H )-one (Compound 42 )

Step 1: Synthesis of (R )-3-(4-ethynyl-2-hydroxyphenyl)-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-methyl-1,2,4-trioxan-5( 4H )-one

( R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (300 mg, 0.92 mmol, 1.0 eq), bromoethanol (172 mg, 1.38 mmol, 3.0 eq.) and TEA (279 mg, 2.76 mmol, 5.0 eq) were dissolved in 1,4-dioxane (10 mL) and reacted at 100°C for 1 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (DCM:MeOH=10:1) and then slurried with EA (5 mL) to obtain the product (170 mg, yield: 50%).

¹ H NMR (400 MHz, CD ₃ OD) δ(ppm): 7.35-7.33(d, 1H), 7.12-7.10(d, 1H), 7.06(s, 1H), 4.29-4.26 (m, 1H), 3.82-3.79 (t, 2H), 3.64 (s, 1H), 3.41 (s, 1H), 3.35 (s, 3H), 3.09 (s, 1H), 2.94 (s, 2H), 2.78-2.68 (m, 2H), 2.00 (s, 1H), 1.98-1.95 (m, 1H), 1.87-1.81 (m, 1H), 1.78-1.68 (m, 1H).

Molecular formula: C ₁₉ H ₂₃ N ₅ O _3Exact molecular weight: 369.18 LC-MS (Pos, m/z ) = 370.15 [M+H] ⁺ .

Example 5: Synthesis of 5-( bromoethynyl )-2-(6-((( cis )-3- hydroxy -3- methylcyclobutyl ) amino )-4- methylpyridin - 3- yl ) phenol ( Compound 34)

Step 1: Synthesis of the intermediate ( cis )-3-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclobutane-1-ol

Dissolve 3,6-dichloro-4-methylthiazolidine (1 g, 6.13 mmol, 1.0 eq) in n-butanol (5 mL), add ( cis )-3-amino-1-methylcyclobutane-1-ol hydrochloride (844 mg, 6.13 mmol, 1.0 eq) and DIPEA (1.5 g, 12.27 mmol, 2.0 eq) in sequence, and stir at 150°C in a microwave for 2 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, water (5 mL) was added, and dichloromethane (5 mL×3) was used for extraction. The organic phase was dried and filtered. The filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 80:1~20:1) to obtain the product (225 mg, yield: 16.1%).

Step 2: Synthesis of the intermediate 3-(ethoxymethoxy)-4-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridin-3-yl)benzaldehyde

The ( cis )-3-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclobutane-1-ol (500 mg, 2.20 mmol, 1.0 eq) obtained in the previous step was dissolved in 1,4-dioxane (5 mL) and water (2 mL). 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (874 mg, 2.85 mmol, 1.3 eq), sodium bicarbonate (370 mg, 4.40 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (161 mg, 0.22 mmol, 0.1 eq) were added in sequence. The mixture was stirred at 90°C for 2 h under nitrogen protection. The reaction was complete as determined by LC-MS. The reaction solution was filtered through diatomaceous earth, washed with ethyl acetate, the organic phase was dried, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=40:1~10:1) to obtain the product (700 mg, yield: 85.7%).

Step 3: Synthesis of the intermediate ( cis )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutane-1-ol

3-(Ethoxymethoxy)-4-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridin-3-yl)benzaldehyde (350 mg, 0.94 mmol, 1.0 eq) was dissolved in methanol (4 mL), and dimethyl (1-diazo-2-oxopropyl)phosphonate (217 mg, 1.13 mmol, 1.2 eq) and potassium carbonate (260 mg, 1.88 mmol, 2.0 eq) were added in sequence and stirred at room temperature for 2 h. LC-MS detected that the reaction was complete, the reaction solution was concentrated, water (5 mL) was added, and dichloromethane (5 mL×3) was extracted. The organic phase was dried and concentrated to obtain the product (330 mg, yield: 95.5%).

Step 4: Synthesis of the intermediate ( cis )-3-((6-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutane-1-ol

( cis )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutane-1-ol (200 mg, 0.54 mmol, 1.0 eq) was dissolved in acetone (3 mL), and silver nitrate (46 mg, 0.27 mmol, 0.5 eq) and NBS (214 mg, 0.65 mmol, 1.2 eq) were added in sequence, and stirred at room temperature for 3 h. LC-MS detected that the reaction was complete, and dichloromethane was added to dilute the reaction solution, and diatomaceous earth was filtered. The filtrate was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane: 7% ammonia methanol = 20:1) to obtain the product (160 mg, yield: 66.4%).

Step 5: Synthesis of compound 5-(bromoethynyl)-2-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridin-3-yl)phenol

The ( cis )-3-((6-(4-(bromoethynyl)-2-(ethoxymethoxy)phenyl)-5-methylphthalimide-3-yl)amino)-1-methylcyclobutane-1-ol (160 mg, 0.36 mmol, 1.0 eq) obtained in the previous step was dissolved in dichloromethane (2 mL), and a 4 mol/L hydrogen chloride/1,4-dioxane solution (0.45 mL) was added. The mixture was stirred at room temperature for 30 min. The reaction was complete as determined by LC-MS. The reaction solution was poured into water, and the pH value was adjusted to 8 with solid sodium bicarbonate. The solution was separated, extracted with dichloromethane (5 mL×2), dried, filtered, and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane: 7% ammonia methanol = 15:1) to obtain the product (80 mg, yield: 57.2%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.16 (s, 1H), 7.18-7.17 (m, 1H), 7.04-6.98 (m, 3H), 6.62 (s, 1H), 4.99 (s, 1H), 3.93-3.86 (m, 1H), 2.44-2.39 (m, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 2H), 1.29 (s, 3H).

Molecular formula: C ₁₈ H ₁₈ BrN ₃ O ₂ Exact molecular weight: 387.06 LC-MS ( m / z ): 388.04 [M+H] ⁺

Example 6: Synthesis of ( R )-2-(6-((1-(3- hydroxypropyl ) piperidin -3 - yl ) amino )-4- methylpiperidin - 3- yl )-5-( prop -1- yn -1- yl ) phenol (Compound 35 )

Step 1: Synthesis of (R )-3-((6-chloro-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-4-methylthiazolidine (5.0 g, 30.67 mmol, 1.0 eq), ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (6.1 g, 30.67 mmol, 1.0 eq) and N , N -diisopropylethylamine (7.9 g, 61.34 mmol, 2.0 q) were added to N , N -dimethylacetamide (20.0 mL) and stirred at 120°C for 6 h. The reaction was complete as monitored by TLC. The system was cooled to room temperature and water (100.0 mL) and EA (100.0 mL) were added. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether: ethyl acetate = 10:1~5:1) to obtain the product (1.5 g, yield: 15.0%).

Step 2: Synthesis of (R )-6-chloro-5-methyl- N- (piperidin-3-yl)piperidin-3-amine

( R )-3-((6-chloro-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.58 mmol, 1.0 eq) was added to dichloromethane (2.0 mL), and a solution of hydrogen chloride-1,4-dioxane (4.0 mol/L, 4.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 h. The reaction was completed as monitored by TLC. The system was adjusted to pH = 7-8 with a saturated sodium bicarbonate aqueous solution, extracted with dichloromethane (100.0 mL), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the product (980.0 mg, yield: 94.5%).

Step 3: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine

( R )-6-Chloro-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (1.40 g, 6.18 mmol, 1.0 eq), 2-ethoxymethoxy-4-propyl-1-ynylphenylboronic acid (1.73 g, 7.42 mmol, 1.2 eq), Pd(dppf) _Cl2 (452 mg, 0.618 mmol, 0.1 eq) and _NaHCO3 (1.04 g, 12.4 mmol, 2.0 eq) were added to 1,4-dioxane (30 mL) in sequence, _H2O (15 mL) was added, and the mixture was heated to 110 ^o C under nitrogen protection for 2 h. The mixture was cooled to room temperature, quenched by adding water (50 mL), extracted with EA (40 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (1.82 g, yield: 77.5%).

Step 4: Synthesis of (R )-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)propan-1-ol

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in DCM (10 mL), triethylamine (353 mg, 3.49 mmol, 5.0 eq) and 3-bromopropanol (548 mg, 3.49 mmol, 5.0 eq) were added, and stirred at room temperature for 20 h. The crude product was concentrated and purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (165 mg, yield: 47.7%).

Step 5: Synthesis of (R )-2-(6-((1-(3-hydroxypropyl)piperidin-3-yl)amino)-4-methylpiperidin-3-yl)-5-(prop-1-yn-1-yl)phenol

( R )-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylphthalimide-3-yl)amino)piperidin-1-yl)propan-1-ol (160 mg, 0.365 mmol, 1.0 eq) was dissolved in DCM (4 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.27 mL, 1.85 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, and then extracted with DCM (10 mL×3). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=5:1) to obtain the product (76.0 mg, yield: 54.8%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.07 (s, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.96-6.89 (m, 3H), 6.71 (s, 1H), 4.30 (s, 1H), 3.48-3.45 (m, 3H), 3.35 (s, 4H), 2.95 (s, 2H), 2.05 (s, 3H), 2.03 (s, 3H), 1.94 (s, 2H), 1.79 (s, 3H), 1.51 (s, 1H).

Molecular formula: C ₂₂ H ₂₈ N ₄ O ₂ Exact molecular weight: 380.22 LC-MS (Pos, m/z ) = 381.26 [M + H] ⁺ .

Example 7: Synthesis of ( R )-2-(6-((1-(2- hydroxy -2- methylpropyl ) piperidin -3- yl ) amino )-4 - methylpiperidin - 3- yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 36)

Step 1: Synthesis of (R )-1-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)-2-methylpropan-2-ol

( R )-6-(2-(Ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyridin-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in DMF (10 mL), _K2CO3 ( ₂₁₈ mg, 1.58 mmol, 2.0 eq) and 1-chloro-2-methyl-2-propanol (171 mg, 1.58 mmol, 2.0 eq) were added, and the mixture was heated to 90°C for 20 h. Water (50 mL) was added to quench the reaction mixture, and the mixture was extracted with EA (20 mL×2). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (262 mg, yield: 73.4%).

Step 2: Synthesis of (R )-2-(6-((1-(2-hydroxy-2-methylpropyl)piperidin-3-yl)amino)-4-methylpiperidin-3-yl)-5-(prop-1-yn-1-yl)phenol

( R )-1-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)-2-methylpropane-2-ol (260 mg, 0.574 mmol, 1.0 eq) was dissolved in DCM (5 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.43 mL, 1.72 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 h, and a saturated aqueous solution of _NaHCO3 was added to adjust the pH to 8. DCM (10 mL) was then used to precipitate the mixture. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=100:1~10:1) to obtain the product (170 mg, yield: 75.0%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.02 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.90-6.88 (m, 2H), 6.67 (s, 1H), 6.56 (d, J = 8.2 Hz, 1H), 4.08 (s, 1H), 4.06-4.03 (m, 1H), 3.00 (d, J = 9.0 Hz, 1H), 2.73 (d, J = 10.6Hz, 1H), 2.27-2.14 (m, 4H), 2.05 (s, 3H), 2.03 (s, 3H), 1.83-1.80 (m, 1H), 1.70-1.67 (m, 1H), 1.56-1.52 (m, 1H), 1.30-1.24 (m, 1H), 1.09 (s, 6H).

Molecular formula: C ₂₃ H ₃₀ N ₄ O ₂ Exact molecular weight: 394.24 LC-MS (Pos, m/z ) = 395.23 [M + H] ⁺ .

Example 8: Synthesis of 2-(6-((( 3R )-1-(1- hydroxypropan -2- yl ) piperidin -3- yl ) amino )-4 - methylpiperidin - 3- yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 37)

Step 1: Synthesis of 2-(( R )-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)propan-1-ol

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (300 mg, 0.788 mmol, 1.0 eq) was dissolved in MeOH (10 mL), 1-hydroxy-2-propanone (87.4 mg, 1.18 mmol, 1.5 eq) was added, and the reaction was carried out at room temperature for 0.5 h. _NaBH3CN (74.2 mg, 1.18 mmol, 1.5 eq) was then added, and the reaction was carried out at room temperature for 2 h. Concentrate, add saturated NaHCO ₃ aqueous solution, extract with DCM (20 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (192 mg, yield: 55.5%).

Step 2: Synthesis of 2-(6-((( 3R )-1-(1-hydroxypropan-2-yl)piperidin-3-yl)amino)-4-methylpiperidin-3-yl)-5-(prop-1-yn-1-yl)phenol

2-(( R )-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)propan-1-ol (192 mg, 0.438 mmol, 1.0 eq) was dissolved in DCM (4 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.33 mL, 1.31 mmol, 3.0 eq) was added dropwise. The mixture was stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated aqueous solution of _NaHCO3 . DCM (10 mL×3) extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (DCM:MeOH=80:1) to obtain the product (125 mg, yield: 75.0%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.03(s, 1H), 7.13(d, J =8.2Hz, 1H), 6.90-6.88(m, 2H), 6.68(s, 1H), 6.61-6.56(m, 1H), 4.25(s, 1H), 4.03-4.01 (m, 1H), 3.48-3.41 (m, 1H), 3.26-3.23 (m, 1H), 2.94-2.87 (m, 1H), 2.64-2.63 (m, 2H), 2.23-2.19 (m, 2H), 2.05 (s, 3H), 2.03 (s, 3H), 1.80-1.79 (m, 1H), 1.71-1.69 (m, 1H), 1.52-1.47 (m, 1H), 1.40-1.34 (m, 1H), 0.91-0.89 (m, 3H).

Molecular formula: C ₂₂ H ₂₈ N ₄ O ₂ Exact molecular weight: 380.22 LC-MS (Pos, m/z ) = 381.22 [M + H] ⁺ .

Example 9: Synthesis of ( R )-1-(2-(3-((6-(2- hydroxy -4-( prop -1- yn - 1- yl ) phenyl )-5 -methylpyridin -3- yl ) amino ) piperidin -1- yl ) ethyl ) urea ( Compound 38)

Step 1: Synthesis of (R )-1-(2-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)ethyl)urea

( R )-6-(2-(Ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyridin-3-amine (300 mg, 0.788 mmol, 1.0 eq), 1-(2-chloroethyl)urea (194 mg, 1.58 mmol, 2.0 eq) and _K2CO3 ( ₂₁₈ mg, 1.58 mmol, 2.0 eq) were added to DMF (10 mL) and heated to 90°C for 20 h. Water (30 mL) was added to quench the reaction mixture, and the mixture was extracted with DCM (20 mL×5). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (146 mg, yield: 39.7%).

Step 2: Synthesis of (R )-1-(2-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)ethyl)urea

( R )-1-(2-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)ethyl)urea (146 mg, 0.313 mmol, 1.0 eq) was dissolved in DCM (4 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 1 mL) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated aqueous solution of NaHCO ₃ , and then extracted with DCM (10 mL×5). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (DCM:MeOH=6:1) to obtain the product (62.0 mg, yield: 48.5%).

¹ H NMR (400 MHz, DMSO- d ₆ )δ(ppm): 10.03(s, 1H), 7.14 (d, J =7.8Hz, 1H), 6.90-6.88 (m, 2H), 6.67 (s, 1H), 6.58 (d, J =7.8Hz, 1H), 5.88-5.86 (m, 1H), 5.49 (s, 2H), 4.05-4.03 (m, 1H), 3.14-3.04 (m, 2H), 2.92 (d, J = 8.8 Hz, 1H), 2.66 (d, J =10.0Hz, 1H), 2.36-2.32 (m, 2H), 2.05 (s, 4H), 2.03 (s, 4H), 1.87-1.84 (m, 1H), 1.72-1.69 (m, 1H), 1.55-1.52 (m, 1H), 1.40-1.34 (m, 1H).

Molecular formula: C ₂₂ H ₂₈ N ₆ O ₂ Exact molecular weight: 408.23 LC-MS (Pos, m/z ) = 409.23 [M + H] ⁺ .

Example 10: Synthesis of ( R )-3-((6-(2- hydroxy -4-( prop -1- yn -1- yl ) phenyl )-5 -methylpiperidin - 3- yl ) amino )-1,1 -dimethylpiperidinium chloride ( Compound 49)

Step 1: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpiperidin-3-yl)amino)-1,1-dimethylpiperidinium iodide

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (120 mg, 0.304 mmol, 1.0 eq) was dissolved in DCM (3 mL), iodomethane (216 mg, 1.52 mmol, 5.0 eq) was added, and the reaction was carried out at room temperature for 5 days. The crude product was concentrated and purified by reverse phase preparative chromatography (ACN: _H2O =3:7) to obtain the product (115 mg, yield: 70.5%).

Step 2: Synthesis of (R )-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpiperidin-3-yl)amino)-1,1-dimethylpiperidinium chloride

( R )-3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpiperidin-3-yl)amino)-1,1-dimethylpiperidinium iodide (105 mg, 0.196 mmol, 1.0 eq) was added to DCM (2 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.15 mL, 3.0 eq) was added dropwise and stirred at room temperature for 1 h. The crude product was concentrated and purified by preparative thin layer chromatography (DCM:MeOH=5:1) to obtain the product (28.0 mg, yield: 37.0%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 11.10 (s, 1H), 8.71 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 1.0 Hz, 1H), 7.07-7.05 (m, 1H), 4.48 (s, 2H), 4.12 (s, 1H), 3.99 (s, 3H), 3.39 (s, 4H), 2.08-2.06 (s, 3H), 2.06 (s, 3H), 1.88 (s, 2H), 1.73 (s, 1H), 1.52 (s, 1H).

Molecular formula: C ₂₁ H ₂₇ ClN ₄ O Exact molecular weight: 386.19 Cation molecular weight: 351.22

LC-MS (Pos, m/z ) = 351.25 [M + H] ⁺ .

Example 11: Synthesis of ( R )-5- ethynyl -3- methyl -2-(6-((1- methylpiperidin -3- yl ) amino ) thiazol - 3- yl ) phenol ( Compound 41)

Step 1: Synthesis of intermediate 4-amino-3-iodo-5-methylbenzoic acid methyl ester

Dissolve methyl 4-amino-3-methylbenzoate (20.0 g, 121.07 mmol, 1.0 eq) in N , N -dimethylformamide (200 mL), add N -iodosuccinimide (29.94 g, 133.18 mmol, 1.1 eq) in batches, react at 25°C for 30 min, and detect the completion of the reaction by TLC. Pour the reaction solution into water (300 mL), extract with methyl tert-butyl ether (200 mL×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1~40:1) to obtain the product (21.3 g, yield: 60.4%).

Step 2: Synthesis of intermediate 4-bromo-3-iodo-5-methylbenzoic acid methyl ester

Dissolve methyl 4-amino-3-iodo-5-methylbenzoate (19.22 g, 66.03 mmol, 1.0 eq) in hydrobromic acid (100 mL). Slowly add sodium nitrite (5.01 g, 72.63 mmol, 1.1 eq) in water (100 mL) at 0°C. After addition, react at 0°C for 30 min. Add cuprous bromide (11.37 g, 79.24 mmol, 1.2 eq) in hydrobromic acid (100 mL). After addition, react at 0°C for 10 min. The reaction is complete by TLC. The reaction solution was dropped into ice water (400 mL), extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1~20:1) to obtain the product (16.2 g, yield: 70.9 %).

Step 3: Synthesis of intermediate 4-bromo-3-hydroxy-5-methylbenzoic acid

Methyl 4-bromo-3-iodo-5-methylbenzoate (12.0 g, 34.68 mmol, 1.0 eq) was dissolved in DMSO (60 mL). 2-Hydroxyacetic acid (791 mg, 10.40 mmol, 0.3 eq), copper hydroxide (338 mg, 3.468 mmol, 0.1 eq) and an aqueous solution (60 mL) of sodium hydroxide (8.32 g, 208.08 mmol, 6.0 eq) were added sequentially. The mixture was reacted at 120°C for 6 h under nitrogen protection. The reaction was complete as detected by TLC. The reaction solution was poured into ice water (120 mL), the pH value was adjusted to 1 with 2 mol/L hydrochloric acid, extracted with methyl tert-butyl ether (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product which was directly used in the next step.

Step 4: Synthesis of intermediate 4-bromo-3-hydroxy-5-methylbenzoic acid methyl ester

Dissolve the crude 4-bromo-3-hydroxy-5-methylbenzoic acid (34.68 mmol) in methanol (80 mL), slowly add sulfoxide chloride (40 mL) dropwise, and after the addition is complete, the reaction is basically complete as determined by TLC. Concentrate the reaction solution, and purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1~20:1) to obtain the product (4.18 g, two-step yield: 49.2 %).

Step 5: Synthesis of intermediate 4-bromo-3-ethoxymethoxy-5-methylbenzoic acid methyl ester

Dissolve 4-bromo-3-hydroxy-5-methylbenzoic acid methyl ester (4.18 g, 17.06 mmol, 1.0 eq) in tetrahydrofuran (40 mL). Add sodium hydroxide (1.03 g, 25.59 mmol, 1.5 eq) in batches at 0°C. React at 0°C for 30 min. Slowly add chloromethyl ethyl ether (2.52 g, 25.59 mmol, 1.5 eq) to the reaction solution. React at 0°C for 5 min. TLC indicates that the reaction is complete. Pour the reaction solution into saturated ammonium chloride aqueous solution (50 mL), extract with methyl tert-butyl ether (40 mL×3), combine the organic phases, dry, and concentrate to obtain the product, which is directly used in the next step (5.17 g crude product, yield: 100%).

Step 6: Synthesis of the intermediate 4-bromo-3-ethoxymethoxy-5-methylphenylmethanol

Dissolve methyl 4-bromo-3-ethoxymethoxy-5-methylbenzoate (3.67 g, 12.11 mmol, 1.0 eq) in tetrahydrofuran (30 mL). Slowly add 1.5 mol/L diisobutylaluminum hydroxide toluene solution (25 mL, 36.33 mmol, 3.0 eq) dropwise at -78°C. After addition, heat the temperature to 25°C and react for 30 min. The reaction is complete as determined by TLC. The reaction solution was cooled to 0°C, methyl tert-butyl ether (30 mL) was added for dilution, water (1.5 mL), 15% sodium hydroxide aqueous solution (1.5 mL) and water (3.6 mL) were added dropwise in sequence to quench the reaction, the temperature was raised to 25°C and stirred for 15 min, anhydrous magnesium sulfate was added for drying, stirring was continued for 15 min, filtered through diatomaceous earth, the filtrate was concentrated to obtain the crude product, which was directly used in the next step.

Step 7: Synthesis of the intermediate 4-bromo-3-ethoxymethoxy-5-methylbenzaldehyde

Dissolve 4-bromo-3-ethoxymethoxy-5-methylphenylmethanol (crude, 12.11 mmol, 1.0 eq) in dichloromethane (40 mL), add manganese dioxide (10.53 g, 121.1 mmol, 10.0 eq), react at room temperature 25°C for 5 h, and the reaction is complete as determined by TLC. Filter the reaction solution through diatomaceous earth, concentrate the crude product, and directly use it in the next step.

Step 8: Synthesis of the intermediate 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

Dissolve the crude 4-bromo-3-ethoxymethoxy-5-methylbenzaldehyde (12.11 mmol, 1.0 eq) in 1,4-dioxane (35 mL), and add pinacol diborate (4.61 g, 18.17 mmol, 1.5 eq), potassium acetate (2.38 g, 24.22 mmol, 2.0 eq) and PdCl ₂ (dppf) (886 mg, 1.211 mmol, 0.1 eq) in sequence. Under nitrogen protection, heat to 110°C for 13 h. The reaction is complete as determined by TLC. The reaction solution was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 90:1~5:1) to obtain the product (1.36 g, three-step yield: 35.8%).

Step 9: Synthesis of the intermediate ( R )-3-ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)benzaldehyde

6-Chloro- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (400 mg, 1.76 mmol, 1.0 eq) was dissolved in 1,4-dioxane (10 mL). 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (788 mg, 2.46 mmol, 1.4 eq), an aqueous solution (2 mL) of potassium carbonate (487 mg, 3.52 mmol, 2.0 eq) and PdCl ₂ (dppf) (322 mg, 0.44 mmol, 0.25 eq) were added sequentially. The temperature was raised to 95°C for 13 h under nitrogen protection. The reaction was complete as detected by TLC. The reaction solution was filtered through diatomaceous earth and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~10:1) to obtain the product (265 mg, yield: 39.1 %).

Step 10: Synthesis of intermediate ( R )-6-(2-(ethoxymethoxy)-4-ethynyl-6-methylphenyl) -N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-3-ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)phthalimide-3-yl)benzaldehyde (265 mg, 0.689 mmol, 1.0 eq) was dissolved in methanol (3 mL), potassium carbonate (191 mg, 1.378 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (199 mg, 1.034 mmol, 1.5 eq) were added successively, and the mixture was reacted at 25°C for 0.5 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1~10:1) to obtain the product (230 mg, yield: 87.8 %).

Step 11: Synthesis of compound ( R )-5-ethynyl-3-methyl-2-(6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)phenol

( R )-3-Ethoxymethoxy-5-methyl-4-(6-(1-methylpiperidin-3-amino)phthalimide-3-yl)benzaldehyde (230 mg, 0.605 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL) and slowly added dropwise into a 4 mol/L hydrogen chloride/1,4-dioxane solution (3 mL). The mixture was reacted at 25°C for 0.5 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, and a saturated sodium bicarbonate aqueous solution (10 mL) was added thereto, and the mixture was extracted with dichloromethane (10 mL×6). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (91 mg, yield: 46.7 %).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.86 (s, 1H), 7.25-7.23 (d, 1H), 7.01 (s, 1H), 6.91-6.88 (m, 3H), 4.25-4.24 (s, 1H), 4.13 (s, 1H), 3.18-3.17 (m, 1H), 2.98 (m, 1H), 2.54 (s, 3H), 2.05 (s, 3H), 1.92-1.86 (m, 2H), 1.73-1.70 (m, 1H), 1.46 (m, 1H), 1.26-1.24 (m, 2H).

Molecular formula: C ₁₉ H ₂₂ N ₄ O Exact molecular weight: 322.18 LC-MS ( m / z ): 323.15 [M+H] ⁺

Example 12: Synthesis of 2-(6-(((1 R , 2 S )-2- hydroxycyclohexyl ) amino )-4- methylpyridin - 3 - yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 43)

Step 1: Synthesis of (1 R ,2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

3,6-Dichloro-4-methylthiazolidine (4.5 g, 27.61 mmol, 1.0 eq.), (1 R ,2 S )-2-aminocyclohexane-1-ol hydrochloride (5.0 g, 33.12 mmol, 1.2 eq) and N , N -diisopropylethylamine (7.13 g, 55.22 mmol, 2.0 eq) were added to N , N -dimethylacetamide (15.0 mL) and stirred at 120 ° C for 48 h. The reaction was not complete as monitored by TLC. The mixture was cooled to room temperature and water (100.0 mL) and EA (100.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane:methanol = 130:1~60:1) to obtain the product (1.2 g, yield: 18.0%).

Step 2: Synthesis of (1 R , 2 S )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

(1 R ,2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol (320.0 mg, 1.32 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (371.8 mg, 1.58 mmol, 1.2 eq), sodium bicarbonate (222.2 mg, 2.64 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (96.8 mg, 0.13 mmol, 0.1 eq) were added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was reacted at 110°C for 3 h under nitrogen protection. The reaction was complete as monitored by TLC. Water (100.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane: methanol = 100:1~60:1) to obtain the product (400.0 mg, yield: 76.4%).

Step 3: Synthesis of 2-(6-(((1 R ,2 S )-2-hydroxycyclohexyl)amino)-4-methylpyridin-3-yl)-5-(prop-1-yn-1-yl)phenol

(1 R ,2 S )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylphthalimide-3-yl)amino)cyclohexane-1-ol (390.0 mg, 0.98 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and a hydrogen chloride/1,4-dioxane solution (4.0 mol/L, 4.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH value was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane: methanol = 100:1-60:1) to obtain the product (130.0 mg, yield: 39.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.06 (s, 1H), 7.13-7.11 (d, J =8 Hz, 1H), 6.90-6.88 (m, 2H), 6.77 (s, 1H), 6.32-6.30 (d, J =8 Hz, 1H), 4.67-4.66 (d, J =4 Hz, 1H), 3.98-3.90 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.75-1.47 (m, 6H), 1.33-1.24 (m, 2H).

Molecular formula: C ₂₀ H ₂₃ N ₃ O ₂ Exact molecular weight: 337.18 LC-MS (Pos, m/z ) = 338.15 [M + H] ⁺ .

Example 13: Synthesis of ( R )-2-(4- cyclopropyl -6-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino ) pyrimidine -3- yl )-5-( propyl -1- yn - 1- yl ) phenol ( Compound 44)

Step 1: Synthesis of (R )-2-(3-((6-chloro-5-cyclopropylpyridin-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-6-chloro-5-cyclopropyl- N- (piperidin-3-yl)pyrimidine-3-amine (310.0 mg, 1.22 mmol, 1.0 eq), bromoethanol (459.7 mg, 3.67 mmol, 3.0 eq) and triethylamine (372.2 mg, 3.67 mmol, 3.0 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 24 h. The reaction was completed as monitored by TLC. The product was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane:methanol = 40:1~10:1) to obtain the product (300.0 mg, yield: 81.4%).

Step 2: Synthesis of (R )-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(propyl-1-yn-1-yl)phenyl)pyrimidine-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-2-(3-((6-chloro-5-cyclopropylpyridin-3-yl)amino)piperidin-1-yl)ethan-1-ol (295.0 mg, 0.99 mmol, 1.0 eq.), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (279.1 mg, 1.19 mmol, 1.2 eq.), sodium bicarbonate (166.9 mg, 1.98 mmol, 2.0 eq.) and Pd(dppf) _Cl2 (72.4 mg, 0.09 mmol, 0.1 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (10-nitropropene) (20-nitropropene) (3-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (20-nitropropene) (3 ...

Step 3: Synthesis of (R )-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)pyrimidine-3-yl)-5-(propyl-1-yn-1-yl)phenol

( R )-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-(propyl-1-yn-1-yl)phenyl)thiazol-3-yl)amino)piperidin-1-yl)ethan-1-ol (234.0 mg, 0.51 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and hydrogen chloride/1,4-dioxane solution (4.0 mol/L, 4.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH value was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (80.0 mg, yield: 39.4%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.99 (s, 1H), 7.20-7.18 (d, J =8 Hz, 1H), 6.91-6.89 (m, 2H), 6.51 (s, 1H), 6.31 (s, 1H), 4.43-4.36 (m, 1H), 4.07 (s, 1H), 3.52-3.51 (m, 2H), 2.94 (s, 1H), 2.67-2.62 (m, 1H), 2.40-2.46 (m, 2H), 2.12-2.05 (m, 5H), 1.80-1.24 (m, 5H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H).

Molecular formula: C ₂₃ H ₂₈ N ₄ O ₂ Exact molecular weight: 392.22 LC-MS (Pos, m/z ) = 393.20 [M + H] ⁺ .

Example 14: Synthesis of 2-(6-(((1 S , 2 R )-2- hydroxycyclohexyl ) amino )-4- methylpyridin - 3 - yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 48)

Step 1: Synthesis of (1 S ,2 R )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

3,6-Dichloro-4-methylthiazolium (3.8 g, 23.31 mmol, 1.0 eq), (1 S ,2 R )-2-aminocyclohexane-1-ol hydrochloride (4.59 g, 30.30 mmol, 1.3 eq) and N , N -diisopropylethylamine (6.0 g, 46.62 mmol, 2.0 eq) were added to N , N -dimethylacetamide (15.0 mL), stirred at 120 ° C for 48 h, TLC monitoring reaction was not complete, cooled to room temperature, added water (100.0 mL), extracted with EA (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, dichloromethane: methanol = 130: 1 ~ 50: 1) to obtain the product (864.0 mg, yield: 15.4%).

Step 2: Synthesis of (1 S , 2 R )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

(1 S ,2 R )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol (300.0 mg, 1.24 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (348.6 mg, 1.48 mmol, 1.2 eq), sodium bicarbonate (208.5 mg, 2.48 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (90.8 mg, 0.12 mmol, 0.1 eq) were added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was reacted at 110°C for 3 h under nitrogen protection. The reaction was complete as monitored by TLC. Water (100.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the product (630.0 mg crude product), which was used directly in the next step.

Step 3: Synthesis of 2-(6-(((1 S , 2 R )-2-hydroxycyclohexyl)amino)-4-methylpyridin-3-yl)-5-(prop-1-yn-1-yl)phenol

(1 S ,2 R )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylphthalimide-3-yl)amino)cyclohexane-1-ol (630.0 mg crude product, 1.24 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and hydrogen chloride/1,4-dioxane solution (4.0 mol/L, 4.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH value was adjusted to 8-9 with saturated sodium carbonate aqueous solution. Dichloromethane (100.0 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain the product (100.0 mg, yield: 23.9%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.05 (s, 1H), 7.13-7.11 (d, J =8 Hz, 1H), 6.90-6.88 (m, 2H), 6.77 (s, 1H), 6.33-6.31 (d, J =8 Hz, 1H), 4.67-4.66 (d, J =4 Hz, 1H), 3.98-3.90 (m, 2H), 2.05 (s, 3H), 2.02 (s, 3H), 1.75-1.46 (m, 6H), 1.33-1.24 (m, 2H).

Molecular formula: C ₂₀ H ₂₃ N ₃ O ₂ Exact molecular weight: 337.18 LC-MS (Pos, m/z ) = 338.17 [M + H] ⁺ .

Example 15: Synthesis of ( R )-5-(2,2 -difluorovinyl )-2-(4- methyl -6-((1- methylpiperidin -3- yl ) amino ) thiazol - 3- yl ) phenol ( Compound 39)

Step 1: Synthesis of 1-bromo-4-(2,2-difluorovinyl)-2-(ethoxymethoxy)benzene

4-Bromo-3-(ethoxymethoxy)benzaldehyde (2.0 g, 7.71 mmol, 1.0 eq) and ethyl 2,2-difluoro-2-(triphenylphosphinoyl)acetate (3.3 g, 9.26 mmol, 1.2 eq) were added to N , N -dimethylformamide (10.0 mL) and stirred at 40°C for 12 h. TLC monitored the reaction to be complete, water (50.0 mL) was added, ethyl acetate (100.0 mL) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether: ethyl acetate = 100:1) to obtain the product (1.0 g, yield: 44.2%).

Step 2: Synthesis of 2-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolancyclopentane

1-Bromo-4-(2,2-difluorovinyl)-2-(ethoxymethoxy)benzene (1.0 g, 3.41 mmol, 1.0 eq), pinacol diborate (1.3 g, 5.11 mmol, 1.5 eq), potassium acetate (669.5 mg, 6.82 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (249.5 mg, 0.34 mmol, 0.1 eq) were added to 1,4-dioxane (15.0 mL). The mixture was reacted at 100°C for 4 h under nitrogen protection. The reaction was complete as monitored by TLC. Water (50.0 mL) and ethyl acetate (100.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (silica gel specification: 100-200 mesh, petroleum ether: ethyl acetate = 20:1) to obtain the product (630.0 mg, yield: 54.3).

Step 3: Synthesis of (R )-6-chloro-5-methyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-6-chloro-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (980.0 mg, 4.32 mmol, 1.0 eq), aqueous formaldehyde solution (37%, 526.2 mg, 6.48 mmol, 1.5 eq) and acetic acid (0.5 mL) were added to methanol (20.0 mL). The mixture was stirred at room temperature for 0.5 h, and then sodium cyanoborohydride (407.4 mg, 6.48 mmol, 1.5 eq) was added and reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The system was concentrated under reduced pressure and a saturated sodium bicarbonate aqueous solution (100.0 mL) was added and stirred for 0.5 h. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40:1~20:1) to obtain the product (750.0 mg, yield: 72.1%).

Step 4: Synthesis of (R )-6-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-6-chloro-5-methyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (230.0 mg, 0.95 mmol, 1.0 eq.), 2-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389.9 mg, 1.14 mmol, 1.2 eq.), sodium bicarbonate (160.4 mg, 1.91 mmol, 2.0 eq.) and Pd(dppf) _Cl2 (34.9 mg, 0.04 mmol, 0.05 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-hydroxy-2-nitropropene) and 4-nitropropene (2-hydroxy-2-nitropropene) (4 ...

Step 5: Synthesis of ( R )-5-(2,2-difluorovinyl)-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)phenol :

( R )-6-(4-(2,2-difluorovinyl)-2-(ethoxymethoxy)phenyl)-5-methyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (140.0 mg, 0.33 mmol, 1.0 eq.) was added to dichloromethane (4.0 mL), and a hydrogen chloride/1,4-dioxane solution (4.0 mol/L, 2.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH value was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (60.0 mg, yield: 49.8%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.00 (s, 1H), 7.19-7.17 (d, J =8 Hz, 1H), 6.97 (s, 1H), 76.91-6.89 (d, J =8 Hz, 1H), 6.68 (s, 1H), 6.64-6.62 (d, J =8 Hz, 1H), 5.83-5.75 (m, 1H), 4.06 (s, 1H), 2.95 (s, 1H), 2.66 (s, 1H), 2.25 (s, 3H), 2.12-1.95 (m, 5H), 1.87-1.34 (m, 4H).

Molecular formula: C ₁₉ H ₂₂ F ₂ N ₄ O Exact molecular weight: 360.18 LC-MS (Pos, m/z ) = 361.19 [M + H] ⁺ .

Example 16: Synthesis of ( R )-2-(7-(1- methylpiperidin -3- yl ) amino ) pyrazolo [1,5- d ][1,2,4] trioxan - 4- yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 40)

Step 1: Synthesis of 1-bromo-2-methoxy-4-(prop-1-yn-1-yl)benzene

1-Bromo-4-iodo-2-methoxybenzene (15.65 g, 50 mmol, 1.0 eq), DIPEA (9.7 g, 75 mmol, 1.5 eq), bis(triphenylphosphine)palladium dichloride (3.5 g, 5 mmol, 0.1 eq) and cuprous iodide (1.9 g, 10 mmol, 0.2 eq) were added to anhydrous THF (150 mL). Under nitrogen protection, 1 mol/L propyne solution in THF (55 mL) was added and the reaction was carried out at room temperature for 64 h. TLC monitoring showed no starting material. Water (100 mL) and ethyl acetate (100 mL) were added, stirred for 5 min, filtered, the filter cake was washed with ethyl acetate, separated, the organic phase was retained, the aqueous phase was extracted with ethyl acetate (100 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (EA: PE = 1: 100) to obtain the product (11.1 g, yield: 99.1%).

Step 2: Synthesis of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)magnesium bromide

Add magnesium bars (1.3 g, 52.19 mmol, 1.1 eq) to anhydrous THF (50 mL), heat to 70°C under nitrogen protection, add 1,2-dibromoethane (1 mL), dropwise add a solution of 1-bromo-2-methoxy-4-(prop-1-yn-1-yl)benzene (10.68 g, 47.45 mmol, 1.0 eq) in anhydrous THF (30 mL), and react at 70°C for 1 h. According to the theoretical amount, proceed to the next step.

Step 3: Synthesis of (2-methoxy-4-(propyl-1-yn-1-yl)phenyl)(1-(4-methoxybenzyl) -1H -pyrazol-5-yl)methanone

Heat a solution of (2-methoxy-4-(prop-1-yn-1-yl)phenyl)magnesium bromide (47.45 mmol, 1.63 eq) in anhydrous THF to 70°C, add dropwise a solution of N -methoxy-1-(4-methoxybenzyl) -N -methyl- 1H -pyrazole-5-carboxamide (8 g, 29.06 mmol, 1.0 eq) in anhydrous THF (20 mL), and react at 70°C for 20 h. TLC monitoring showed that there was a lot of residual raw material. The temperature was cooled to room temperature, saturated aqueous ammonium chloride solution (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:100~1:5) to obtain the product (1 g, yield: 9.5%).

Step 4: Synthesis of (2-methoxy-4-(propyl-1-yn-1-yl)phenyl)( 1H -pyrazol-5-yl)methanone

(2-Methoxy-4-(propyl-1-yn-1-yl)phenyl)(1-(4-methoxybenzyl) -1H -pyrazol-5-yl)methanone (1.6 g, 4.44 mmol, 1.0 eq) was added to a mixed solution of 1,2-dichloroethane (10 mL) and TFA (10 mL), and the mixture was heated to reflux for 7 h. No starting material was found by TCL monitoring, the mixture was concentrated under reduced pressure, a saturated aqueous sodium carbonate solution (50 mL) was added, and the mixture was extracted with DCM (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10~1:3) to obtain the product (1.0 g, yield: 90.9%).

Step 5: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5- d ][1,2,4]trioxan-7-ol

(2-Methoxy-4-(propyl-1-yn-1-yl)phenyl)( 1H -pyrazol-5-yl)methanone (1.0 g, 4.16 mmol, 1.0 eq), methyl carbazate (1.1 g, 12.48 mmol, 3.0 eq) and acetic acid (249.6 mg, 4.16 mmol, 1.0 eq) were added to anhydrous methanol (50 mL) and heated to reflux for 72 h. LC-MS detected no starting material, the mixture was concentrated under reduced pressure, anhydrous ethanol (50 mL) was added, and then sodium hydroxide (499.2 mg, 12.48 mmol, 3.0 eq) with a mass fraction of 60% was added, and the mixture was heated to reflux for 16 h. LC-MS monitoring showed no starting material. The solution was concentrated under reduced pressure, water (50 mL) was added, 2 mol/L hydrochloric acid was added dropwise until pH = 3, and the solution was extracted with DCM (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.2 g, yield: 100%).

Step 6: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5- d ][1,2,4]trioxan-7-thiol

4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5 -d ][1,2,4]trioxan-7-ol (1.2 g, 14.16mmol, 1.0 eq) and Lawson reagent (1.7 g, 4.16 mmol, 1.0 eq) were added to xylene (150 mL) and heated to 110°C for 19h under nitrogen protection. TCL monitoring showed that there was no starting material, and the temperature was lowered to room temperature, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (MeOH:DCM=1:100) to obtain the product (1.1 g, yield: 91.6%).

Step 7: Synthesis of 4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-7-(methylthio)pyrazolo[1,5- d ][1,2,4]triazine

4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)pyrazolo[1,5 -d ][1,2,4]trioxan-7-thiol (1.1 g, 3.71 mmol, 1.0 eq) was added to DMA (5 mL), anhydrous potassium carbonate (512 mg, 3.71 mmol, 1.0 eq) and iodomethane (1 g, 7.42 mmol, 2.0 eq) were added, and the mixture was heated to 60°C for 3 h. TLC monitoring showed no starting material. The reaction solution was poured into ice water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain the product (200 mg, yield: 18.2%).

Step 8: Synthesis of (R )-3-((4-(2-methoxy-4-(propyl-1-yn-1-yl)phenyl)pyrazolo[1,5- d ][1,2,4]trioxan-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

4-(2-methoxy-4-(prop-1-yn-1-yl)phenyl)-7-(methylthio)pyrazolo[1,5- d ][1,2,4]triazine (200 mg, 0.64 mmol, 1.0 eq) and 3A molecular sieve (500 mg) were added to anhydrous DCM (5 mL), and a DCM (5 mL) solution of mCPBA (mass fraction 85%, 324.8 mg, 1.6 mmol, 2.5 eq) previously dried with 3A molecular sieve was added dropwise, and the mixture was reacted at room temperature for 1 h. No starting material was found by TLC monitoring, and a DCM (2 mL) solution of ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (897.2 mg, 4.48 mmol, 7.0 eq) was added, and the mixture was reacted at room temperature for 16 h. TCL detection showed no raw material, water (30 mL) was added, and the mixture was extracted with DCM (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:PE=1:10~1:2) to obtain the product (146 mg, two-step yield: 49.3%).

Step 9: Synthesis of (R )-2-(7-(piperidin-3-ylamino)pyrazolo[1,5- d ][1,2,4]trioxan-4-yl)-5-(prop-1-yn-1-yl)phenol

( R )-3-((4-(2-methoxy-4-(propyl-1-yn-1-yl)phenyl)pyrazolo[1,5- d ][1,2,4]trioxan-7-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (146 mg, 0.31 mmol, 1.0 eq) was added to anhydrous DCM (10 mL), cooled to -50°C, boron tribromide (776.6 mg, 3.1 mmol, 10 eq) was added dropwise, and the temperature was naturally raised to room temperature for reaction for 23 h. No starting material was detected by LC-MS monitoring, methanol (10 mL) was added dropwise, stirred for 10 min, concentrated under reduced pressure, added with saturated sodium bicarbonate aqueous solution (30 mL), and washed with DCM (30 mL). mL×3) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (108 mg, yield: 100%).

Step 10: Synthesis of (R )-2-(7-(1-methylpiperidin-3-yl)amino)pyrazolo[1,5- d ][1,2,4]trioxan-4-yl)-5-(prop-1-yn-1-yl)phenol

( R )-2-(7-(Piperidin-3-ylamino)pyrazolo[1,5 -d ][1,2,4]trioxan-4-yl)-5-(prop-1-yn-1-yl)phenol (108 mg, 0.31 mmol, 1.0 eq) was added to methanol (5 mL), and 37% formaldehyde aqueous solution (25.2 mg, 0.31 mmol, 1.0 eq) was added, and the reaction was carried out at room temperature for 0.5 h. Sodium cyanoborohydride (19.5 mg, 0.31 mmol, 1.0 eq) was added, and the reaction was carried out at room temperature for 1 h. TCL monitoring showed no starting material. The solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution (20 mL) was added, and the solution was extracted with DCM (20 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (MeOH:DCM=1:10) to obtain the product (67 mg, yield: 59.7%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 12.65 (s, 1H), 8.41 (s, 1H), 7.87-7.85 (d, 2H), 7.31 (s, 1H), 6.99 (d, 2H), 4.35-4.33 (m, 1H), 2.83-2.81 (m, 1H), 2.51 (m, 1H), 2.23 (m, 4H), 2.08 (m, 4H), 1.82 (m, 1H), 1.73-1.68 (m, 2H), 1.59-1.56 (m, 1H).

Molecular formula: C ₂₀ H ₂₂ N ₆ O Exact mass: 362.19 LC-MS (Pos, m/z ) =363.31 [M+H] ⁺ .

Example 17: ( R )-2-(4- cyclopropyl -6-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 45)

Step 1: Synthesis of (R )-4-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde

( R )-2-(3-((6-chloro-5-cyclopropyl-pyridin-3-yl)amino)piperidin-1-yl)ethyl-1-ol (237 mg, 0.799 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (318 mg, 1.04 mmol, 1.3 eq), an aqueous solution (1 mL) of sodium bicarbonate (134 mg, 1.598 mmol, 2.0 eq) and _PdCl2 (dppf) (58 mg, 0.0799 mmol, 0.1 eq) were added thereto. The temperature was raised to 90 °C for 1 h under nitrogen protection. h, TLC detected that the reaction was complete. The reaction solution was concentrated, and dichloromethane (10 mL) and water (10 mL) were added to the concentrated solution, and the liquids were separated. The aqueous phase was extracted with dichloromethane (10 mL×3), and the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~20:1) to obtain the product (120 mg, yield: 34.1%).

Step 2: Synthesis of (R )-2-(3-((5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)pyrimidine-3-yl)amino)piperidin-1-yl)ethyl-1-ol

( R )-4-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde (120 mg, 0.273 mmol, 1.0 eq) was dissolved in methanol (2 mL). Potassium carbonate (75 mg, 0.546 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (79 mg, 0.41 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 30 min. The reaction was complete as detected by TLC. The reaction solution was concentrated, and a saturated sodium chloride aqueous solution (5 mL) was added to the concentrated solution. The mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was directly used in the next step.

Step 3: Synthesis of (R )-2-(4-cyclopropyl-6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)thiazin-3-yl)-5-ethynylphenol

( R )-2-(3-((5-cyclopropyl-6-(2-ethoxymethoxy)-4-ethynylphenyl)thiazol-3-yl)amino)piperidin-1-yl)ethyl-1-ol (crude, 0.273 mmol) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 15 min. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane: ammonia in methanol = 15:1) to obtain the product (21 mg, two-step yield: 20.4%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.08 (s, 1H), 7.24-7.22 (m, 1H), 7.01-7.00 (m, 2H), 6.63 (s, 1H), 6.32 (s, 1H), 4.19 (d, 2H), 3.59 (s, 2H), 3.11-2.77 (m, 2H), 2.69-2.57 (m, 1H), 2.39-2.18 (m, 2H), 1.91-1.71 (m, 2H), 1.67-1.65 (m, 1H), 1.59-1.53 (m, 1H), 1.40-1.39 (m, 1H), 1.34-1.17 (m, 2H), 0.90-0.86 (m, 2H), 0.63-0.60 (m, 2H).

Molecular formula: C ₂₂ H ₂₆ N ₄ O ₂ Exact molecular weight: 378.21 LC-MS ( m/z ): 379.26 [M+H] ⁺ .

Example 18: Synthesis of ( R )-2-(4- cyclopropyl -6-((1- ethylpiperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 90)

Step 1: Synthesis of (R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (piperidin-3-yl)pyrimidine-3-amine

( R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)thiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.03 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). 2,6-Lutidine (1.74 g, 16.24 mmol, 8.0 eq) and trimethylsilyl trifluoromethanesulfonate (1.8 g, 8.12 mmol, 4.0 eq) were added dropwise at 0°C. The reaction was completed by TLC. Water (20 mL) was added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 50:1~10:1) to obtain 1.15 g (crude product).

Step 2: Synthesis of (R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (1-ethylpiperidin-3-yl)pyrimidine-3-amine

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (piperidin-3-yl)pyrimidine-3-amine (400 mg crude product, 0.703 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), triethylamine (356 mg, 3.515 mmol, 5.0 eq) and iodoethane (548 mg, 3.515 mmol, 5.0 eq) were added thereto, and the mixture was reacted at 25°C for 16 h. The reaction was completed by TLC detection. Dichloromethane (7 mL) and water (10 mL) were added to the reaction solution, and the liquids were separated. The aqueous phase was extracted with dichloromethane (10 mL × 2). The organic phases were combined and dried. The crude product was purified by preparative thin layer chromatography (dichloromethane: ammonia methanol solution = 15:1) to obtain the product (150 mg, yield: 50.7 %).

Step 3: Synthesis of (R )-2-(4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)thiazol-3-yl)-5-ethynylphenol

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (1-ethylpiperidin-3-yl)pyrimidine-3-amine (150 mg, 0.357 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 5 min and the reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane: ammonia methanol solution = 10:1) to obtain the product (28 mg, yield: 21.7%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.09 (s, 1H), 7.25-7.23 (d, 1H), 7.01-7.00 (m, 2H), 6.47-6.45 (d, 1H), 6.33 (s, 1H), 4.18 (s, 1H), 4.03-4.01 (m, 1H), 2.93-2.91 (m, 1H), 2.61 (m, 1H), 2.37-2.32 (m, 2H), 2.03-2.02 (m, 1H), 1.91-1.81 (m, 2H), 1.71-1.69 (m, 1H), 1.59-1.48 (m, 2H), 1.34-1.26 (m, 1H), 1.02-0.98 (t, 3H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H).

Molecular formula: C ₂₂ H ₂₆ N ₄ O Exact molecular weight: 362.21 LC-MS ( m/z ): 363.29 [M+H] ⁺ .

Example 19: Synthesis of ( R )-2-(4- cyclopropyl -6-((1 -cyclopropylpiperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 95)

Step 1:

( R )-2-(4-cyclopropyl-6-(piperidin-3-ylamino)thiazol-3-yl)-5-ethynylphenol (crude product, 0.75mmol, 1.0eq) was dissolved in methanol (3mL), 1-ethoxy-1-trimethylsilyloxycyclopropane (523mg, 3.0mmol, 4.0eq) and cesium fluoride (228mg, 1.5mmol, 2.0eq) were added thereto, the temperature was raised to 50℃ and the reaction was carried out for 1h, sodium cyanoborohydride (189mg, 3.0mmol, 4.0eq) was added thereto, the reaction was carried out at 50℃ for 10 min, and the reaction was completed by TLC detection. The reaction solution was concentrated, and a saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, and extracted with dichloromethane (10 mL×3). The organic phases were combined, dried, and concentrated to obtain a crude product, which was purified by preparative thin layer chromatography (dichloromethane: methanol solution of ammonia = 10:1) to obtain the product (15 mg, yield: 5.3 %).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.08 (s, 1H), 7.24-7.22 (m, 1H), 7.01-7.00 (m, 2H), 6.46 (s, 1H), 6.32 (s, 1H), 4.18 (s, 1H), 3.97 (s, 1H), 3.07 (s, 1H), 2.76 (s, 1H), 2.33 (s, 1H), 2.19 (s, 1H), 1.82 (s, 1H), 1.67 (s, 2H), 1.59-1.50 (m, 1H), 1.48 (m, 1H), 1.34-1.33 (m, 1H), 0.89-0.85 (m, 2H), 0.63-0.60 (m, 2H), 0.44-0.35 (m, 4H).

Molecular formula: C ₂₃ H ₂₆ N ₄ O Exact molecular weight: 374.21 LC-MS ( m/z ): 375.29 [M+H] ⁺ .

Example 20: Synthesis of ( R )-2-(4- cyclopropyl -6-((1-( methyl - d ₃ ) piperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 85)

Step 1: Synthesis of compound ( R )-5 _- cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (1-(methyl- d3 )piperidin-3-yl)pyridin-3-amine

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (piperidin-3-yl)pyrimidine-3-amine (400 mg crude product, 0.703 mmol, 1.0 eq) was dissolved in dichloromethane (3 mL), triethylamine (356 mg, 3.515 mmol, 5.0 eq) and deuterated iodomethane (296 mg, 3.515 mmol, 5.0 eq) were added thereto, and the mixture was reacted at 25°C for 2 h (LC-MS detected that the reaction rate of the raw material was 60%). Water (10 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 mL). The aqueous phase was extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol solution of ammonia = 15:1) to obtain the product (125 mg, yield: 43.4 %).

Step 2: Synthesis of compound ( R )-2-(4-cyclopropyl-6-((1-(methyl- d3 )piperidin-3-yl)amino)thiazol-3-yl)-5 _- ethynylphenol

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenol) -N- (1-(methyl- d3 )piperidin- ₃ -yl)pyrimidine-3-amine (125 mg, 0.305 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 15 min and the reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane: ammonia methanol solution = 10:1) to obtain the product (40 mg, yield: 37.4%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.11 (s, 1H), 7.23-7.21 (d, 1H), 7.02-7.00 (m, 2H), 6.68-6.67 (d, 1H), 6.34 (s, 1H), 4.19 (s, 1H), 4.15 (m, 1H), 3.11 (m, 1H), 2.83 (m, 1H), 2.41-2.29 (m, 2H), 1.84-1.79 (m, 2H), 1.66-1.63 (m, 1H), 1.59-1.53 (m, 1H), 1.44-1.30 (m, 1H), 0.91-0.83 (m, 2H), 0.65-0.58 (m, 2H).

Molecular formula: C ₂₁ H ₂₁ D ₃ N ₄ O Exact molecular weight: 351.21 LC-MS ( m / z ): 352.22 [M+H] ⁺ .

Example 21: Synthesis of ( R )-3-((6-(2- hydroxy -4-( prop -1- yn -1- yl ) phenyl )-5- methylpyridin - 3- yl ) amino ) piperidine -1 -carboximidamide trifluoroacetate ( Compound 46)

Step 1: Synthesis of tert-butyl (R )-(((tert-butyloxycarbonyl)imino)(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)methyl)carbamate

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)carbamate-3-amine (400.0 mg, 1.05 mmol, 1.0 eq.) and tert-butyl (((tert-butyloxycarbonyl)amino)( 1H -pyrazol-1-yl)methylene)carbamate (391.5 mg, 1.26 mmol, 1.2 eq.) were added to methanol (10.0 mL) and stirred at room temperature for 3 h. The reaction was complete as monitored by TLC. The product was concentrated under reduced pressure and purified by silica gel column chromatography (dichloromethane:methanol=100:1~60:1) to obtain the product (400.0 mg, yield: 61.1%).

Step 2: Synthesis of (R )-3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidine-1-carboximidamide trifluoroacetate

( R )-(((tert-butyloxycarbonyl)imino)(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylcarbamate-3-yl)amino)piperidin-1-yl)methyl)carbamate (340.0 mg, 0.54 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), and trifluoroacetic acid (5.0 mL) was added dropwise. The reaction was carried out at room temperature for 4 h. The reaction was complete as monitored by LC-MS. Water (30.0 mL) was added, and the mixture was extracted with dichloromethane (100.0 mL). The aqueous phase was purified by reverse phase column chromatography (water:acetonitrile = 4:6) to obtain the product (180.0 mg, yield: 69.2%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.55 (s, 1H), 8.72 (s, 1H), 7.57 (s, 4H), 7.37-7.36 (m, 1H), 7.20-7.18 (d, J =8 Hz, 1H), 6.98-6.95 (m, 2H), 3.99-3.98 (m, 1H), 3.90-3.87 (m, 1H), 3.69-3.66 (m, 1H), 3.24-3.13 (m, 2H), 2.17 (s, 3H), 2.06 (s, 4H), 1.85-1.83 (m, 1H), 1.67-1.55 (m, 2H).

Molecular formula: C ₂₂ H ₂₅ F ₃ N ₆ O ₃ free base exact molecular weight: 364.20 LC-MS (Pos, m/z ) = 365.21 [M + H] ⁺ .

Example 22: Synthesis of ( R )-5- ethynyl -2-(4- isopropyl -6-((1- methylpiperidin -3- yl ) amino ) thiazol - 3- yl ) phenol ( Compound 81)

Step 1: Synthesis of 3,6-dichloro-4-isopropylpyridamole

3,6-Dichlorothiazolium (10.0 g, 67.12 mmol, 1.0 eq), isobutyric acid (5.9 g, 67.12 mmol, 1.0 eq) and silver nitrate (11.4 g, 67.12 mmol, 1.0 eq) were added to water (100 mL), and the temperature was raised to 50°C. Concentrated sulfuric acid (11.0 mL) was added dropwise, and then an aqueous solution (100.0 mL) of ammonium persulfate (45.9 g, 201.36 mmol, 3.0 eq) was added dropwise. The temperature was raised to 70°C and the reaction was carried out for 2 h. The reaction was complete after TLC detection. The mixture was cooled, filtered, and the filtrate was washed with 2.0 The pH value was adjusted to 9 with 1.5 mol/L sodium hydroxide aqueous solution, extracted with ethyl acetate (400 mL), the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (10.1 g, yield: 78.9%).

Step 2: Synthesis of (R )-3-((6-chloro-5-isopropylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-4-isopropylpiperidinium (5.0 g, 26.17 mmol, 1.0 eq), ( R )-1-tert-butyloxycarbonyl-3-aminopiperidinium (5.76 g, 28.79 mmol, 1.1 eq) and N , N -diisopropylethylamine (6.7 g, 52.34 mmol, 2.0 eq) were added to N , N -dimethylacetamide (50.0 mL) and reacted at 120°C for 72 h. The reaction was complete after TLC detection. Ethyl acetate (200.0 mL) and water (100 mL), the organic phase was dried, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=200:1~20:1) to obtain the product (3.8 g, yield: 40.9%).

Step 3: Synthesis of (R )-6-chloro-5-isopropyl- N- (piperidin-3-yl)pyrimidine-3-amine

( R )-3-((6-chloro-5-isopropylpyridinium-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3.7 g, 10.43 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 10.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 h, and the reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with a saturated sodium carbonate aqueous solution, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (2.5 g, yield: 96.1%).

Step 4: Synthesis of (R )-6-chloro-5-isopropyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-6-chloro-5-isopropyl- N- (piperidin-3-yl)pyrimidine-3-amine (860.0 mg, 3.37 mmol, 1.0 eq) and aqueous formaldehyde solution (mass fraction 37%, 356.1 mg, 4.38 mmol, 1.3 eq) were added to methanol (12.0 mL). After stirring at room temperature for 1 h, sodium cyanoborohydride (318.1 mg, 5.05 mmol, 1.5 eq) was added and the reaction was continued at room temperature for 2 h. The reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (100.0 mL) was added and stirred for 0.5 h. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 50:1~10:1) to obtain the product (770.0 mg, yield: 84.9%).

Step 5: Synthesis of (R )-3-(ethoxymethoxy)-4-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)benzaldehyde

( R )-6-chloro-5-isopropyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (352.5 mg, 1.31 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (441.6 mg, 1.44 mmol, 1.1 eq), sodium bicarbonate (220.0 mg, 2.62 mmol, 2.0 eq) and Pd(dppf) _Cl2 (47.9 mg, 0.06 mmol, 0.05 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20 ...6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (20-nitropropene) (20-nitropropene) (3-nitropropene) (40-nitropropene) (5-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (20-nitropropene) (3-nitropropene) (

Step 6: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-isopropyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-3-(Ethoxymethoxy)-4-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)phthalimide-3-yl)benzaldehyde (223.0 mg, 0.54 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (155.7 mg, 0.81 mmol, 1.5 eq) and anhydrous potassium carbonate (149.2 mg, 1.08 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. The reaction was complete as monitored by LC-MS. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1~10:1) to obtain the product (200.0 mg, yield: 90.9%).

Step 7: Synthesis of (R )-5-ethynyl-2-(4-isopropyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)phenol

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-isopropyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (200.0 mg, 0.49 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 5.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (110.0 mg, yield: 64.3%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.90 (s, 1H), 7.15-7.13 (d, J =8Hz, 1H), 7.00-6.99 (m, 2H), 6.77-6.73 (m, 2H), 4.17 (s, 2H), 3.13 (s, 1H), 2.82(s, 1H), 2.65-2.59 (m, 1H), 2.50 (s, 3H), 2.41 (s, 3H), 1.89-1.80 (m, 2H), 1.66-1.64 (m, 1H), 1.03-1.01 (m, 6H).

Molecular formula: C ₂₁ H ₂₆ N ₄ O Exact molecular weight: 350.21 LC-MS ( m/z ): 351.25 [M+H] ⁺ .

Example 23: Synthesis of ( R )-5- ethynyl -2-(4- cyclobutyl -6-((1- methylpiperidin -3- yl ) amino ) piperidin - 3- yl ) phenol ( Compound 82)

Step 1: Synthesis of 3,6-dichloro-4-cyclobutylpyridinium

3,6-Dichlorothiazolium (10.0 g, 67.12 mmol, 1.0 eq), cyclobutyric acid (6.7 g, 67.12 mmol, 1.0 eq) and silver nitrate (11.4 g, 67.12 mmol, 1.0 eq) were added to water (100 mL), and the temperature was raised to 50°C. Concentrated sulfuric acid (11.0 mL) was added dropwise, and then an aqueous solution (100.0 mL) of ammonium persulfate (45.9 g, 201.36 mmol, 3.0 eq) was added dropwise. The temperature was raised to 70°C and the reaction was carried out for 2 h. The reaction was complete after TLC detection. The mixture was cooled and filtered. The filtrate was adjusted to pH 9 with 2.0 mol/L sodium hydroxide solution. Ethyl acetate (400 mL) for extraction, the organic phase was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (9.8 g, yield: 72.0%).

Step 2: Synthesis of (R )-3-((6-chloro-5-cyclobutylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-4-cyclobutylpiperidinium (5.0 g, 24.62 mmol, 1.0 eq), ( R )-1-tert-butyloxycarbonyl-3-aminopiperidinium (7.4 g, 36.93 mmol, 1.5 eq) and N , N -diisopropylethylamine (6.3 g, 49.24 mmol, 2.0 eq) were added to N , N -dimethylacetamide (50.0 mL) and reacted at 120°C for 72 h. The reaction was complete after TLC detection. Ethyl acetate (200.0 mL) was added and the mixture was washed with water (100 mL). A saturated aqueous solution of ammonium chloride (100 mL) was added. mL), the organic phase was dried, filtered, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=200:1~100:1) to obtain the product (1.8 g, yield: 20.0 %).

Step 3: Synthesis of (R )-6-chloro-5-cyclobutyl- N- (piperidin-3-yl)piperidin-3-amine

( R )-3-((6-chloro-5-cyclobutylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.8 g, 4.91 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 10.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with a saturated sodium carbonate aqueous solution, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.2 g, yield: 92.3%).

Step 4: Synthesis of (R )-6-chloro-5-cyclobutyl- N- (1-methylpiperidin-3-yl)piperidin-3-amine

( R )-6-chloro-5-cyclobutyl- N- (piperidin-3-yl)pyrimidine-3-amine (1.17 g, 4.38 mmol, 1.0 eq) and aqueous formaldehyde solution (mass fraction 37%, 462.7 mg, 5.69 mmol, 1.3 eq) were added to methanol (15.0 mL), stirred at room temperature for 1 h, sodium cyanoborohydride (413.3 mg, 6.57 mmol, 1.5 eq) was added, and the reaction was carried out at room temperature for 2 h. The reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure. A saturated aqueous sodium bicarbonate solution (100.0 mL) was added and stirred for 0.5 h. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 50:1~10:1) to obtain the product (1.1 mg, yield: 91.6%).

Step 5: Synthesis of (R )-3-(ethoxymethoxy)-4-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)benzaldehyde

( R )-6-chloro-5-cyclobutyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (330.0 mg, 1.17 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (395.8 mg, 1.28 mmol, 1.1 eq), sodium bicarbonate (197.4 mg, 2.34 mmol, 2.0 eq) and Pd(dppf) _Cl2 (42.9 mg, 0.06 mmol, 0.05 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (6-nitropropene) (10-nitropropene) (2-nitropropene) (3-nitropropene) (6-nitropropene) (3-nitropropene) (6-nitropropene) (7-nitropropene) (6-nitropropene) (3 ...6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6-nitropropene) (6

Step 6: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclobutyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-3-(Ethoxymethoxy)-4-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)benzaldehyde (314.0 mg, 0.74 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (213.1 mg, 1.11 mmol, 1.5 eq) and anhydrous potassium carbonate (204.2 mg, 1.48 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. The reaction was complete as monitored by LC-MS. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1~10:1) to obtain the product (280.0 mg, yield: 90.1%).

Step 7: Synthesis of (R )-5-ethynyl-2-(4-cyclobutyl-6-((1-methylpiperidin-3-yl)amino)piperidin-3-yl)phenol

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-cyclobutyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (280.0 mg, 0.66 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 5.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (140.0 mg, yield: 58.0%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.89 (s, 1H), 7.10-7.08 (d, J =8Hz, 1H), 6.97-6.96 (m, 2H), 6.75 (s, 1H), 6.64-6.63 (m, 1H), 4.17 (s, 1H), 4.10-4.08 (m, 1H), 3.39-3.35 (m, 1H), 2.91 (s, 1H), 2.59(s, 1H), 2.23(s, 3H), 2.11(s, 1H), 1.99(s, 1H), 1.88-1.83(m, 6H), 1.81-1.52(m, 4H).

Molecular formula: C ₂₂ H ₂₆ N ₄ O Exact molecular weight: 362.21 LC-MS ( m/z ): 363.26 [M+H] ⁺ .

Example 24: Synthesis of 5- ethynyl -2-(6-(((1 R , 2 R )-2- hydroxycyclohexyl ) amino )-4- methylpyridin -3- yl ) phenol ( Compound 83 )

Step 1: Synthesis of (1 R ,2 R )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

3,6-Dichloro-4-methylthiazolidine (3.2 g, 19.63 mmol, 1.0 eq), (1 R ,2 R )-2-aminocyclohexane-1-ol hydrochloride (3.8 g, 25.52 mmol, 1.3 eq) and N , N -diisopropylethylamine (5.0 g, 39.26 mmol, 2.0 eq) were added to N , N -dimethylacetamide (20.0 mL) and stirred at 120 ° C for 72 h. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature and ethyl acetate (100.0 mL) and water (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=200:1-50:1) to obtain the product (1.2 g, yield: 25.5%).

Step 2: Synthesis of 3-(ethoxymethoxy)-4-(6-(((1 R ,2 R )-2-hydroxycyclohexyl)amino)-4-methylpyridin-3-yl)benzaldehyde

( 1R , 2R )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol (500.0 mg, 2.06 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzaldehyde (696.6 mg, 2.27 mmol, 1.1 eq), sodium bicarbonate (347.4 mg, 4.12 mmol, 2.0 eq) and Pd(dppf) _Cl2 (75.6 mg, 0.10 mmol, 0.05 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (2-nitropropene) (6-nitropropene) (8-nitropropene) (7-nitropropene) (8-nitropropene) (10-nitropropene) (2-nitropropene) (6-nitropropene) (8-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10 ...

Step 3: Synthesis of ( 1R , 2R )-2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

3-(Ethoxymethoxy)-4-(6-(((1 R ,2 R )-2-hydroxycyclohexyl)amino)-4-methylphthalimide-3-yl)benzaldehyde (454.0 mg, 1.18 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (339.4 mg, 1.77 mmol, 1.5 eq) and anhydrous potassium carbonate (325.3 mg, 2.36 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 12 h. The reaction was complete as monitored by TLC. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=60:1~20:1) to obtain the product (447.0 mg, yield: 99.5%).

Step 4: Synthesis of 5-ethynyl-2-(6-(((1 R ,2 R )-2-hydroxycyclohexyl)amino)-4-methylpyridin-3-yl)phenol

(1 R ,2 R )-2-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylphthalimide-3-yl)amino)cyclohexane-1-ol (447.0 mg, 1.17 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 5.0 mL) was added dropwise. The mixture was reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40:1-20:1) to obtain the product (260.0 mg, yield: 68.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.13 (s, 1H), 7.19-7.17 (d, J =8 Hz, 1H), 7.00-6.98 (m, 2H), 6.70 (s, 1H), 6.57-6.55 (d, J =8 Hz, 1H), 4.79-4.78 (d, J =4 Hz, 1H), 4.17 (s, 1H), 3.66-3.64 (m, 1H), 3.38-3.36 (m, 1H), 2.05 (s, 1H), 2.03 (s, 3H), 1.92-1.89 (m, 1H), 1.67-1.62 (m, 2H), 1.34-1.16 (m, 4H).

Molecular formula: C ₁₉ H ₂₁ N ₃ O ₂ Exact molecular weight: 323.16 LC-MS (Pos, m/z ) = 324.21 [M + H] ⁺ .

Example 25: Synthesis of 2-(6-(((1 S , 2 R )-2- hydroxy -2 -methylcyclohexyl ) amino )-4- methylpyridin - 3- yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 80)

Step 1: Synthesis of (1 R ,2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol

3,6-Dichloro-4-methylthiazolidine (3.8 g, 23.33 mmol, 1.0 eq.), (1 R ,2 S )-2-aminocyclohexane-1-ol hydrochloride (4.6 g, 30.33 mmol, 1.3 eq.) and N , N -diisopropylethylamine (9.0 g, 69.99 mmol, 3.0 eq.) were added to N , N -dimethylacetamide (20.0 mL) and stirred at 120 ° C for 72 h. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature and ethyl acetate (100.0 mL) and water (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=200:1~20:1) to obtain the product (1.4 g, yield: 25.0%).

Step 2: Synthesis of (S )-2-((5,6-dimethylthiazol-3-yl)amino)cyclohexane-1-one

N -chlorosuccinimide (2.25 g, 16.89 mmol, 3.0 eq) was added to dichloromethane (20.0 mL), and the temperature was lowered to 0°C under nitrogen protection. Dimethyl sulfide (1.0 g, 16.89 mmol, 3.0 eq) was added dropwise. After reacting for 0.5 hours, the temperature was lowered to -40°C, and a dichloromethane solution (20.0 mL) of (1 R ,2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)cyclohexane-1-ol (1.36 g, 5.63 mmol, 1.0 eq) was added dropwise. After continuing to react at -40°C for 1.5 hours, triethylamine (1.7 g, 16.89 mmol, 3.0 eq), gradually warm to room temperature for reaction for 14 h, the reaction was complete when monitored by TLC, dichloromethane (100.0 mL) was added, washed with water (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~2:1) to obtain the product (1.21 g, yield: 81.4%).

Step 3: Synthesis of (1 R , 2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclohexane-1-ol

( S )-2-((5,6-dimethylthiazol-3-yl)amino)cyclohexane-1-one (995.0 mg, 4.15 mmol, 1.0 eq) was added to dry tetrahydrofuran (15.0 mL). Under nitrogen protection, a solution of methylmagnesium chloride in tetrahydrofuran (3.0 mol/L, 5.5 mL, 16.60 mmol, 4.0 eq) was added dropwise. After reacting for 7 h, ethyl acetate (100.0 mL) was added and the mixture was washed with a saturated aqueous solution of ammonium chloride (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol = 130:1~100:1) to obtain the product (380.0 mg, yield: 35.8%).

Step 4: Synthesis of (1 R , 2 S )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclohexane-1-ol

(1 R ,2 S )-2-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclohexane-1-ol (380.0 mg, 1.48 mmol, 1.0 eq), (2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)boronic acid (417.3 mg, 1.77 mmol, 1.2 eq), sodium bicarbonate (249.6 mg, 2.96 mmol, 2.0 eq) and Pd(dppf)Cl ₂ (54.3 mg, 0.07 mmol, 0.05 eq) were added to a mixed solution of 1,4-dioxane (10.0 mL) and water (5.0 mL). The mixture was reacted at 110°C for 3 h under nitrogen protection. The reaction was complete as monitored by TLC. Water (100.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=150:1~100:1) to obtain the product (210.0 mg, yield: 34.5%).

Step 5: Synthesis of 2-(6-(((1 S , 2 R )-2-hydroxy-2-methylcyclohexyl)amino)-4-methylpyridin-3-yl)-5-(prop-1-yn-1-yl)phenol

(1 R ,2 S )-2-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylphthalimide-3-yl)amino)-1-methylcyclohexane-1-ol (200.0 mg, 0.49 mmol, 1.0 eq) was added to dichloromethane (4.0 mL), and a solution of hydrogen chloride in 1,4-dioxane (4.0 mol/L, 4.0 mL) was added dropwise. The reaction was carried out at room temperature for 12 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (53.0 mg, yield: 30.9%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.04 (s, 1H), 7.14-7.12 (d, J =8 Hz, 1H), 6.90-6.88 (m, 2H), 6.81 (s, 1H), 6.50-6.48 (d, J =8 Hz, 1H), 4.91 (s, 1H), 3.93-3.89 (m, 1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.88-1.86 (m, 1H), 1.70-1.60 (m, 3H), 1.46-1.31 (m, 4H), 1.11 (s, 3H).

Molecular formula: C ₂₁ H ₂₅ N ₃ O ₂ Exact molecular weight: 351.19 LC-MS (Pos, m/z )=352.18[M+H] ⁺ .

Example 26: Synthesis of ( R )-2-(5- cyclopropyl -3-((1 -cyclopropylpiperidin -3 -yl ) amino )-1,2,4- trioxan - 6- yl )-5- ethynylphenol ( Compound 97)

Step 1: Synthesis of (R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-bromo-5-cyclopropyl-1,2,4-trioxaborol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (4.68 g, 11.75 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (4.67 g, 15.27 mmol, 1.3 eq), sodium bicarbonate (1.97 g, 23.50 mmol, 2.0 eq) and Pd(dppf) _Cl2 (428.9 mg, 0.58 mmol, 0.05 eq) were added to 1,4-dioxane (50.0 mL) and water (25.0 mL) was heated to 110°C for 14 h under nitrogen protection. The reaction was complete as monitored by TCL. Water (150 mL) was added and extracted with ethyl acetate (200.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1~60:1) to obtain the product (2.1 g, yield: 36.2%).

Step 2: Synthesis of (R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 4.02 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.1 g, 6.03 mmol, 1.5 eq) and anhydrous potassium carbonate (1.1 g, 8.04 mmol, 2.0 eq) were added to methanol (20.0 mL) and reacted at room temperature for 2 h. The reaction was complete as monitored by TLC. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=130:1~100:1) to obtain the product (1.6 g, yield: 80.8%).

Step 3: Synthesis of (R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (piperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trithiophene-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 3.24 mmol, 1.0 eq) was added to dichloromethane (25.0 mL), 2,6-lutidine (2.0 g, 19.44 mmol, 6.0 eq) was added dropwise, the temperature was lowered to 0°C, trimethylsilyl trifluoromethanesulfonate (2.1 g, 9.72 mmol, 3.0 eq) was added dropwise, the temperature was gradually raised to room temperature and the reaction was carried out for 2 h. The reaction was complete as monitored by TLC, dichloromethane (100.0 mL) and water (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1~20:1) to obtain the product (603.0 mg, yield: 47.2%)

Step 4: Synthesis of (R )-5-cyclopropyl- N- (1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trioxan-3-amine

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (603.0 mg, 1.53 mmol, 1.0 eq), (1-ethoxycyclopropoxy)trimethylsilane (1.0 g, 6.12 mmol, 4.0 eq), csium fluoride (931.0 mg, 6.12 mol, 4.0 eq) and glacial acetic acid (0.5 mL) were added to methanol (20.0 mL), stirred at 50°C for 3 h, and then sodium cyanoborohydride (481.3 mg, 7.65 mmol, 5.0 eq) was added and reacted at 50°C for 12 h. The reaction was complete as monitored by TLC. The mixture was concentrated under reduced pressure. A saturated sodium bicarbonate aqueous solution (100.0 mL) was added and stirred for 0.5 h. The mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product (712.0 mg, yield 100%).

Step 5: Synthesis of (R )-2-(5-cyclopropyl-3-((1-cyclopropylpiperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-5-ethynylphenol

( R )-5-cyclopropyl- N- (1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trioxan-3-amine (712.0 mg crude product, 1.53 mmol, 1.0 eq.) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (10.0 mL) was added dropwise. The reaction was carried out at room temperature for 0.5 h. The reaction was completed as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (50.0 mg, yield: 8.7%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.04 (s, 1H), 7.54 (s, 1H), 7.30-7.28 (d, J =8 Hz, 1H), 7.05-7.02 (m, 2H), 4.21 (s, 1H), 3.98-3.57 (m, 1H), 3.09-3.07 (d, J =8 Hz, 1H), 2.82-2.80 (d, J =8 Hz, 1H), 2.18-1.97 (m, 2H), 1.84-1.82 (m, 1H), 1.70-1.64 (m, 3H), 1.46-1.30 (m, 2H), 1.01-1.09 (m, 4H).

Molecular formula: C ₂₂ H ₂₅ N ₅ O Exact molecular weight: 375.21 LC-MS (m /z ): 376.25 [M+H] ⁺ .

Example 27: Synthesis of ( R )-2-(5- cyclopropyl -3-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino )-1,2,4 -trioxan - 6- yl )-5- ethynylphenol ( Compound 100)

Step 1: Synthesis of (R )-6-bromo-5-cyclopropyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-3-((6-bromo-5-cyclopropyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 6.03 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (5.0 mL) was added dropwise. The reaction was carried out at room temperature for 2 h. The reaction was completed by TLC monitoring. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, and the mixture was extracted with dichloromethane (100.0 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product (1.75 g, yield: 97.7%).

Step 2: Synthesis of (R )-2-(3-((6-bromo-5-cyclopropyl-1,2,4-trioxan-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-6-bromo-5-cyclopropyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (383.0 mg, 1.28 mmol, 1.0 eq), bromoethanol (481.5 mg, 3.84 mmol, 3.0 eq) and triethylamine (519.7 mg, 5.12 mmol, 4.0 eq) were added to dichloromethane (10.0 mL) and stirred at room temperature for 14 h. The reaction was complete after TLC monitoring. Dichloromethane (100.0 mL) and saturated aqueous ammonium chloride solution (50.0 mL) were added. The organic phase was washed with anhydrous sodium sulfate and dried, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1~10:1) to obtain the product (300.0 mg, yield: 68.5%).

Step 3: Synthesis of (R )-4-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde

( R )-2-(3-((6-bromo-5-cyclopropyl-1,2,4-trioxaborol-3-yl)amino)piperidin-1-yl)ethan-1-ol (297.3 mg, 0.87 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (319.0 mg, 1.04 mmol, 1.2 eq), sodium bicarbonate (145.8 mg, 1.73 mmol, 2.0 eq) and Pd(dppf) _Cl2 (31.7 mg, 0.04 mmol, 0.05 eq) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-[4-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[

Step 4: Synthesis of (R )-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trioxan-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-4-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde (160.0 mg, 0.36 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (104.4 mg, 0.54 mmol, 1.5 eq) and anhydrous potassium carbonate (100.0 mg, 0.72 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 12 h. The reaction was complete as monitored by LC-MS. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=50:1~10:1) to obtain the product (141.0 mg, yield: 89.0%).

Step 5: Synthesis of (R )-2-(5-cyclopropyl-3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-5-ethynylphenol

( R )-2-(3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-1,2,4-trioxan-3-yl)amino)piperidin-1-yl)ethan-1-ol (141.0 mg, 0.32 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction was completed as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (60.0 mg, yield: 49.5%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.03 (s, 1H), 7.61-7.53 (m, 1H), 7.30-7.28 (d, J =8 Hz, 1H), 7.05-7.02 (m, 2H), 4.42 (s, 1H), 4.21 (s, 1H), 4.10-3.72 (m, 1H), 3.51-3.48 (m, 2H), 2.91 (s, 1H), 2.67 (s, 1H), 2.40 (s, 2H), 1.78-1.64 (m, 3H), 1.52-1.36 (m, 2H), 1.02-0.96 (m, 4H).

Molecular formula: C ₂₁ H ₂₅ N ₅ O ₂ Exact molecular weight: 379.20 LC-MS (Pos, m/z )=380.24[M+H] ⁺ .

Example 28: Synthesis of ( R )-2-(5- cyclopropyl -3-((1-( methyl - d3 ₎ piperidin -3 - yl ) amino )-1,2,4 -trioxan - 6- yl )-5- ethynylphenol ( Compound 87)

Step 1: Synthesis of (R )-6 _- bromo-5-cyclopropyl- N- (1-(methyl- d3 )piperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-6-bromo-5-cyclopropyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (458.6 mg, 1.54 mmol, 1.0 eq), deuterated iodomethane (891.78 mg, 6.15 mmol, 4.0 eq) and triethylamine (778.1 mg, 7.69 mmol, 5.0 eq) were added to dichloromethane (10.0 mL), stirred at room temperature for 5 h, and dichloromethane (100.0 mL) was added. A saturated aqueous solution of ammonium chloride (50.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=40:1~10:1) to obtain the product (225.0 mg, yield: 46.4%).

( R )-6-bromo-5-cyclopropyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (550.0 mg, 1.84 mmol, 1.0 eq), deuterated iodomethane (1.46 g, 10.12 mmol, 5.5 eq) and triethylamine (1.0 g, 10.12 mmol, 5.5 eq) were added to dichloromethane (10.0 mL), stirred at room temperature for 5 h, and dichloromethane (100.0 mL) was added. A saturated aqueous solution of ammonium chloride (50.0 mL) was added. mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40:1~10:1) to obtain the product (235.5 mg, yield: 40.5%). The two fractions were combined to obtain the product (460.5 mg).

Step 2: Synthesis of (R )-4-(5-cyclopropyl-3-((1-(methyl- d3 )piperidin-3-yl)amino)-1,2,4 _- trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde

( R )-6-bromo-5-cyclopropyl- N- (1-(methyl- d3 )piperidin-3- _yl )-1,2,4-trioxan-3-amine (340.0 mg, 1.08 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (396.2 mg, 1.29 mmol, 1.2 eq), anhydrous potassium carbonate (297.9 mg, 2.16 mmol, 2.0 eq) and Pd( _PPh3 ) ₄ (124.5 mg, 0.11 mmol, 0.1 eq) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20 ...6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (20-nitropropene) (20-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (20-nitropropene) (3-nitropropene) (

Step 4: Synthesis of (R )-5 _- cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-(methyl- d3 )piperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-4-(5-cyclopropyl-3-((1-(methyl- d3 )piperidin-3- _yl )amino)-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde (260.0 mg, 0.63 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (180.7 mg, 0.95 mmol, 1.5 eq) and anhydrous potassium carbonate (173.3 mg, 1.26 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 4 h. The reaction was complete as monitored by LC-MS. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=40:1~10:1) to obtain the product (188.0 mg, yield: 72.7%).

Step 5: Synthesis of (R )-2-(5-cyclopropyl-3-((1-(methyl- d3 )piperidin-3-yl)amino)-1,2,4 _- trioxan-6-yl)-5-ethynylphenol

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-(methyl- d3 )piperidin- ₃ -yl)-1,2,4-trioxan-3-amine (188.0 mg, 0.46 mmol, 1.0 eq) was added to dichloromethane (5.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction was completed as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (110.0 mg, yield: 67.9%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.04 (s, 1H), 7.55-7.43 (m, 1H), 7.30-7.28 (d, J =8 Hz, 1H), 7.05-7.01 (m, 2H), 4.21 (s, 1H), 3.92-3.85 (m, 1H), 2.85-2.84 (m, 1H), 2.62 (s, 1H), 1.92-1.80 (m, 3H), 1.70-1.64 (m, 2H), 1.53-1.50(m, 1H), 1.34-1.23(m, 1H), 1.03-0.95(m, 4H).

Molecular formula: C ₂₀ H ₂₀ D ₃ N ₅ O Exact molecular weight: 352.21 LC-MS (Pos, m/z ) = 353.23 [M + H] ⁺ .

Example 29: Synthesis of ( R )-2-(5- cyclopropyl -3-((1- ethylpiperidin -3- yl ) amino )-1,2,4- trioxan - 6- yl )-5- ethynylphenol ( Compound 92)

Step 1: Synthesis of (R )-6-bromo-5-cyclopropyl- N- (1-ethylpiperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-6-bromo-5-cyclopropyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (920.0 mg, 3.08 mmol, 1.0 eq), iodoethane (4.8 g, 30.8 mmol, 10.0 eq) and triethylamine (3.1 g, 30.8 mmol, 10.0 eq) were added to dichloromethane (20.0 mL), stirred at room temperature for 14 h, and dichloromethane (100.0 mL) was added. A saturated aqueous solution of ammonium chloride (50.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=40:1~10:1) to obtain the product (970.0 mg, yield: 96.4%).

Step 2: Synthesis of ( R )-4-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde

( R )-6-Bromo-5-cyclopropyl- N- (1-ethylpiperidin-3-yl)-1,2,4-trioxan-3-amine (390.0 mg, 1.19 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (366.0 mg, 1.19 mmol, 1.0 eq.), anhydrous potassium carbonate (330.3 mg, 2.38 mmol, 2.0 eq.) and Pd( _PPh3 ) ₄ (138.0 mg, 0.11 mmol, 0.1 eq.) were added to 1,4-dioxane (10.0 mL) and water (4.0 The mixture was added with 4% paraformaldehyde (2-nitropropene) and 4-nitropropene (2-nitropropene) (2-nitropropene) (3-nitropropene) (4-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (10-nitropropene) (20-nitropropene) (20-nitropropene) (6-nitropropene) (7-nitropropene) (8-nitropropene) (9-nitropropene) (20 ...

Step 3: Synthesis of (R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-4-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde (285.0 mg, 0.67 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (192.9 mg, 1.00 mmol, 1.5 eq) and anhydrous potassium carbonate (184.9 mg, 1.34 mmol, 2.0 eq) were added to methanol (15.0 mL) and reacted at room temperature for 4 h. The reaction was complete as monitored by LC-MS. The residue was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=40:1~10:1) to obtain the product (170.0 mg, yield: 60.2%).

Step 4: Synthesis of (R )-2-(5-cyclopropyl-3-((1-ethylpiperidin-3-yl)amino)-1,2,4-trioxan-6-yl)-5-ethynylphenol

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-1,2,4-trioxan-3-amine (170.0 mg, 0.40 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (2.0 mL) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction was complete as monitored by TLC. The pH was adjusted to 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (80.0 mg, yield: 55.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.04 (s, 1H), 7.58-7.56 (m, 1H), 7.30-7.28 (d, J =8 Hz, 1H), 7.05-7.01 (m, 2H), 4.22 (s, 1H), 3.94-3.86 (m, 1H), 2.99-2.97 (m, 1H), 2.72 (s, 1H), 2.36 (s, 2H), 1.93-1.83 (m, 3H), 1.70-1.64 (m, 2H), 1.53-1.47 (m, 1H), 1.40-1.30 (m, 2H),1.02-1.98 (m, 5H), 0.86-0.81 (m, 1H).

Molecular formula: C ₂₁ H ₂₅ N ₅ O Exact molecular weight: 363.21 LC-MS (Pos, m/z ) = 364.22 [M + H] ⁺ .

Example 30: Synthesis of ( R )-6-((1- ethylpiperidin -3- yl ) amino )-3-(4- ethynyl -2- hydroxyphenyl )-4- methyl -1,2,4 - trioxan - 5 ( 4H )-one ( Compound 93)

Step 1: Synthesis of (R )-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (200 mg, 0.61 mmol, 1.0 eq) and a tetrahydrofuran solution of acetaldehyde (5 mol/L, 0.18 mL, 0.92 mmol, 1.5 eq) in methanol (10 mL) and stir at room temperature for 18 h. Add sodium cyanoborohydride (38 mg, 0.61 mmol, 1.0 eq) and react at room temperature for 1 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (10 mL) and extracted with DCM (10 mL×4). The organic phase was dried, concentrated, and purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (50 mg, yield: 23.2%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.47 (s, 1H), 7.32-7.30 (d, 1H), 7.05-7.03 (d, 2H), 6.86 (s, 1H), 4.29 (s, 1H), 4.04-4.03 (d, 1H), 3.18 (s, 3H), 2.82 (s, 1H), 2.59 (s, 1H), 2.42 (s, 2H), 2.19 (s, 2H), 1.71-1.67 (d, 2H), 1.60-1.56 (t, 2H), 1.06-1.00 (t, 3H).

Molecular formula: C ₁₉ H ₂₃ N ₅ O ₂ Exact molecular weight: 353.19 LC-MS (Pos, m/z ) = 354.22 [M+H] ⁺ .

Example 31: Synthesis of ( R )-6-((1- cyclopropylpiperidin -3- yl ) amino )-3-(4- ethynyl -2- hydroxyphenyl )-4- methyl -1,2,4 - trioxan -5( 4H )-one ( Compound 98)

Step 1: Synthesis of (R )-6-((1-cyclopropylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one

( R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxo-5( 4H )-one (200 mg, 0.61 mmol, 1.0 eq), 1-ethoxy-1-trimethylsilylcyclopropane (532 mg, 3.05 mmol, 5.0 eq.) and CsF (140 mg, 0.92 mmol, 1.5 eq) were dissolved in methanol (10 mL) and AcOH (0.5 mL). The mixture was reacted at 50°C for 2 h, sodium cyanoborohydride (153 mg, 2.44 mmol, 4.0 eq) was added and the reaction was continued at 50°C for 1 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (20 mL), the pH was adjusted to about 8 with sodium bicarbonate, and extracted with DCM (20 mL×3). The organic phase was dried, concentrated, and purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (70 mg, yield: 31.4%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.42 (s, 1H), 7.32-7.31 (d, 1H), 7.05-7.02 (t, 2H), 6.78-6.76 (d, 1H), 4.29 (s, 1H), 3.96-3.94 (t, 1H), 3.17 (s, 3H), 2.95-2.93 (d, 1H), 2.68 (s, 1H), 2.33-2.32 (d, 2H), 1.72-1.70 (d, 1H), 1.65-1.55 (m, 3H), 1.49-1.44 (m, 1H), 0.43-0.41 (t, 2H), 0.31 (s, 2H).

Molecular formula: C ₂₀ H ₂₃ N ₅ O ₂ Exact molecular weight: 365.19 LC-MS (Pos, m/z ) = 366.24 [M+H] ⁺ .

Example 32: Synthesis of ( R )-4- cyclopropyl -6-((1- ethylpiperidin -3- yl ) amino )-3-(4- ethynyl -2- hydroxyphenyl )-1,2,4- trioxan - 5( 4H ) -one ( Compound 109)

Step 1: Synthesis of N -cyclopropyl-4-iodo-2-methoxybenzamide

To a solution of cyclopropylamine (15.3 g, 267.93 mmol, 3.0 eq) in DCM (100 mL) was added a solution of 4-iodo-2-methoxybenzyl chloride (26.66 g, 89.91 mmol, 1.0 eq) in DCM (200 mL) and the mixture was reacted at room temperature for 10 min. The reaction was complete as determined by TLC. The reaction solution was poured into water (200 mL) and extracted with DCM (100 mL×2). The organic phase was dried and concentrated to obtain the product (28.51 g, yield: 100%).

Step 2: Synthesis of N -cyclopropyl-4-iodo-2-methoxythiobenzamide

N -cyclopropyl-4-iodo-2-methoxybenzamide (28.51 g, 89.91 mmol, 1.0 eq) and Lawson reagent (20.0 g, 49.45 mmol, 0.55 eq) were dissolved in THF (300 mL) and reacted at 60°C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (EA:PE=1:10) to obtain the product (25 g, yield: 83.4%).

Step 3: Synthesis of N -cyclopropyl-4-iodo-2-methoxythiobenzoylimidate methyl ester

Dissolve N -cyclopropyl-4-iodo-2-methoxythiobenzamide (25 g, 75.03 mmol, 1.0 eq) and iodomethane (21.3 g, 150.06 mmol, 2.0 eq) in THF (300 mL). Reaction at room temperature for 17 h. TLC detection shows that the reaction is complete. Pour the reaction solution into water (500 mL), adjust the pH to about 9 with potassium carbonate, extract with EA (200 mL×2), dry the organic phase, and concentrate to obtain the product (26.05 g, yield: 100%).

Step 4: Synthesis of N -amino- N' -cyclopropyl-4-iodo-2-methoxybenzamidine

Dissolve N -cyclopropyl-4-iodo-2-methoxythiobenzoylimidate (26.05 g, 122.90 mmol, 1.0 eq.) and hydrazine hydrate (8.84 g, 150.06 mmol, 2.0 eq.) in EtOH (300 mL) and react at 80°C for 1 h. The reaction was complete as monitored by LC-MS, and the reaction solution was concentrated under reduced pressure to obtain the product (24.85 g, yield: 100%).

Step 5: Synthesis of 6-amino-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-trioxan-5( 4H )-one

N -amino- N' -cyclopropyl-4-iodo-2-methoxybenzamidine (15 g, 45.29 mmol, 1.0 eq), ethyl thioxamate (9.05 g, 67.94 mmol, 1.5 eq) and TEA (13.75 g, 135.87 mmol, 3.0 eq) were dissolved in EtOH (150 mL) and reacted at 80°C for 4 h. The reaction was complete as monitored by LC-MS, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:PE=1:1) to obtain the product (9.0 g, yield: 51.7%).

Step 6: Synthesis of 6-bromo-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-trioxan-5( 4H )-one

6-amino-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-trioxan-5(4 H )-one (9.0 g, 23.42 mmol, 1.0 eq) and CuBr (6.72 g, 46.84 mmol, 2.0 eq) were dispersed in ACN (90 mL). Under nitrogen protection, tert-butyl nitrite (4.83 g, 46.84 mmol, 2.0 eq) was added dropwise at 70°C and reacted at 70°C for 0.5 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:DCM=1:10) to obtain the product (3.0 g, yield: 28.6%).

Step 7: Synthesis of (R )-3-((4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

6-Bromo-4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-1,2,4-trioxan-5( 4H )-one (3.0g, 6.69mmol, 1.0 eq), ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (2.0g, 10.03mmol, 1.5eq) and DIPEA (1.30g, 10.03mmol, 1.5eq.) were dissolved in 1,4-dioxane (30 mL) and reacted at 100℃ for 18h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure, the crude product was dispersed with water (30mL), extracted with EA (30mL×3), the organic phase was dried and concentrated to obtain the product (3.8g, yield: 100%).

Step 8: Synthesis of (R )-3-((4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Disperse ( R )-3-((4-cyclopropyl-3-(4-iodo-2-methoxyphenyl)-5-oxo-4,5-dihydro-1,2,4-trioxo-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3.8 g, 6.69 mmol, 1.0 eq), trimethylsilylene (3.28 g, 33.45 mmol, 5.0 eq ₎ , PdCl2( _PPh3 ) ₂ (470 mg, 0.67 mmol, 0.1 eq) and CuI (383 mg, 2.01 mmol, 0.3 eq) in diisopropylamine (20 mL) and THF (20 mL). Under nitrogen protection, react at 40℃ for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (EA:PE=1:2) to obtain the product (3.0 g, yield: 83.3 %).

Step 9: Synthesis of (R )-4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-3-((4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 5.57 mmol, 1.0 eq) in EA (30 mL), add a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL), and react at room temperature for 3 h. The reaction was complete as detected by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (20 mL), extracted with EA (20 mL×2), the aqueous phase was retained, the pH value was adjusted to about 8 with sodium bicarbonate, extracted with EA (20 mL×4), the organic phase was dried and concentrated to obtain the product (1.7 g, yield: 70%).

Step 10: Synthesis of (R )-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-trioxan-5( 4H )-one

( R )-4-cyclopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (0.5g, 1.14mmol, 1.0eq), TEA (577mg, 5.70mmol, 5.0eq) and iodoethane (889mg, 5.70mmol, 5.0eq) were dissolved in DCM (10mL) and reacted at room temperature for 19h. LC-MS detected that the reaction was complete, and the reaction solution was poured into water (10mL), extracted with DCM (10mL×3), and the organic phase was dried and concentrated to obtain the product (530mg, yield: 100%).

Step 11: Synthesis of (R )-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-1,2,4-trioxan-5( 4H )-one

( R )-4-cyclopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-trioxan-5( 4H )-one (530 mg, 1.14 mmol, 1.0 eq) was dissolved in DCM (10 mL), cooled to -60°C, and boron tribromide (857 mg, 3.42 mmol, 3.0 eq) was added. The temperature was naturally raised to room temperature for reaction for 3 h. The reaction was complete as detected by TLC. An appropriate amount of methanol was added to the reaction solution to quench it. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (10 mL). The pH value was adjusted to about 8 with sodium bicarbonate. It was extracted with DCM (20 mL×3). The organic phase was dried and concentrated. The crude product was first purified by silica gel column chromatography (DCM:MeOH=20:1) and then purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (240 mg, yield: 55.6%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.34 (s, 1H), 7.34-7.32 (d, 1H), 7.03-6.99 (d, 2H), 6.78-6.76 (d, 1H), 4.26 (s, 1H), 3.97 (s, 1H), 2.99 (s, 1H), 2.77 (s, 1H), 2.51 (s, 1H), 2.36-2.35 (d, 2H), 2.14 (s, 2H), 1.68-1.64 (d, 2H), 1.58-1.51 (m, 2H), 1.01-1.00 (d, 3H), 0.67-0.66 (d, 2H), 0.50 (s, 2H).

Molecular formula: C ₂₁ H ₂₅ N ₅ O ₂ Exact molecular weight: 379.20 LC-MS (Pos, m/z ) = 380.24 [M+H] ⁺ .

Example 33: Synthesis of ( R )-3-(4- ethyl -2- hydroxyphenyl )-4- methyl -6-((1-( methyl _- d3 ) piperidin -3- yl ) amino )-1,2,4 -trioxan - 5( 4H )-one ( Compound 88)

Step 1: Synthesis of (R )-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

( R )-3-((3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (3.0 g, 5.86 mmol, 1.0 eq.) was dissolved in EA (30 mL), and a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 10 mL) was added and the reaction was carried out at room temperature for 2.5 h. The reaction was complete as detected by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dissolved in water (20 mL), extracted with EA (20 mL×2), the aqueous phase was retained, the pH value was adjusted to about 8 with sodium bicarbonate, extracted with EA (30 mL×3), the organic phase was dried and concentrated to obtain the product (2.25 g, yield: 93.3%).

Step 2: Synthesis of (R )-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-((1-(methyl _- d3 )piperidin-3-yl)amino)-1,2,4-trioxan-5( 4H )-one

( R )-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (1.0 g, 2.43 mmol, 1.0 eq) and TEA (1.76 g, 12.15 mmol, 5.0 eq) were dissolved in DCM (30 mL), deuterated iodomethane (1.23 g, 12.15 mmol, 5.0 eq) was added, and the reaction was carried out at room temperature for 10 min. The reaction was complete as determined by TLC, and the reaction solution was poured into water (20 mL), extracted with DCM (20 mL×2), and the organic phase was dried and concentrated to obtain the product (1.04 g, yield: 100%).

Step 3: Synthesis of (R )-3-(4-ethyl-2-hydroxyphenyl)-4-methyl-6-((1-(methyl- d3 )piperidin-3-yl)amino)-1,2,4 _- trioxan-5( 4H )-one

( R )-3-(2-methoxy _- 4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-((1-(methyl- d3 )piperidin-3-yl)amino)-1,2,4-trioxan-5( 4H )-one (1.04 g, 2.43 mmol, 1.0 eq) was dissolved in DCM (20 mL), cooled to -60°C, and boron tribromide (1.83 g, 7.29 mmol, 3.0 eq) was added. The temperature was naturally raised to room temperature for reaction for 5 h. The reaction was complete as detected by LC-MS. An appropriate amount of water was added to the reaction solution for quenching. The solution was extracted with DCM (20 mL×2). The aqueous phase was retained and the pH value was adjusted to about 8 with sodium bicarbonate. The solution was extracted with EA (20 mL×6). The organic phase was dried, concentrated, and purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (160 mg, yield: 19.2%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.44 (s, 1H), 7.32-7.30 (d, 1H), 7.05-7.02 (d, 2H), 6.80-6.78 (d, 1H), 4.28 (s, 1H), 4.04-4.01 (s, 1H), 3.18 (s, 3H), 2.71-2.68 (d, 1H), 2.44 (s, 1H), 2.11 (s, 2H), 1.67 (s, 2H), 1.59-1.48 (m, 2H).

Molecular formula: C ₁₈ H ₁₈ D ₃ N ₅ O _2Exact molecular weight: 342.19 LC-MS (Pos, m/z ) = 343.25 [M+H] ⁺ .

Example 34: Synthesis of ( R )-2-(6-((1 -cyclopropylpiperidin -3 -yl ) amino )-4- methylpiperidin - 3- yl )-5- ethynylphenol ( Compound 94) :

Step 1: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-methylphenyl)-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-chloro-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.20 g, 6.73 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.47 g, 8.08 mmol, 1.2 eq), _PdCl2 (dppf) (0.49 g, 0.67 mmol, 0.1 eq) and sodium bicarbonate (1.13 g, 13.46 mmol, 2.0 eq) were added to a mixed solvent of 1,4-dioxane (40 mL) and water (10 mL). The mixture was heated to 110°C for 2 h under nitrogen protection. The reaction was complete as monitored by TLC. The temperature was lowered to room temperature, water (50 mL) was added, and the mixture was extracted with EA (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM: MeOH = 100:1~10:1) to obtain the product (2.68 g, yield: 84.6%).

Step 2: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylphthalimide-3-yl)amino)piperidine-1-carboxylate (2.68 g, 5.70 mmol, 1.0 eq) and _K2CO3 (1.57 g, 11.39 mmol, 2.0 eq) _were added to methanol (30 mL), stirred and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.64 g, 8.54 mmol, 1.5 eq) was added, and the reaction was carried out at room temperature for 2 h. The reaction was complete as monitored by TLC. The mixture was concentrated, EA (50 mL) was added, and the mixture was washed with water (25 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH =100:1~10:1) to obtain the product (2.32 g, yield: 87.3%).

Step 3: Synthesis of (R )-5-ethynyl-2-(4-methyl-6-(piperidin-3-ylamino)thiazol-3-yl)phenol

( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpiperidine-3-yl)amino)piperidine-1-carboxylate (400.0 mg, 0.86 mmol, 1.0 eq) was dissolved in DCM (4 mL), and a 4 mol/L hydrogen chloride solution in 1,4-dioxane (2.0 mL, 8.14 mmol, 9.5 eq) was added dropwise and reacted at room temperature for 2 h. The reaction was complete as monitored by TLC, and water (2 mL) was added to quench the reaction. The pH was adjusted to 8 with saturated NaHCO ₃ solution, and the mixture was extracted with DCM (5 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (169.8 mg, yield: 64.2%) was purified by preparative thin layer chromatography (DCM:MeOH =10:1).

Step 4: Synthesis of (R )-2-(6-((1-cyclopropylpiperidin-3-yl)amino)-4-methylpiperidin-3-yl)-5-ethynylphenol

( R )-5-ethynyl-2-(4-methyl-6-(piperidin-3-ylamino)thiazol-3-yl)phenol (169.8 mg, 0.55 mmol, 1.0 eq) was dissolved in MeOH (10 mL), (1-ethoxycyclopropoxy)trimethylsilane (383.9 mg, 2.20 mmol, 4.0 eq) and CsF (167.3 mg, 1.10 mmol, 2.0 eq) were added, and the mixture was stirred at 50°C for 1 h. _NaBH3CN (167.3 mg, 1.10 mmol, 2.0 eq) was added, and stirring was continued for 0.5 h. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature, concentrated under reduced pressure, and the crude product was added with saturated aqueous NaHCO ₃ solution (20 mL). The mixture was extracted with DCM (20 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (67.3 mg, yield: 35.1%) was purified by preparative thin layer chromatography (DCM:MeOH = 10:1).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.10 (s, 1H), 7.19-7.17 (m, 1H), 7.00-6.98 (m, 2H), 6.68 (s, 1H), 6.58 (d, J = 6.8 Hz, 1H), 4.19 (s, 1H), 3.96 (s, 1H), 3.10 (s, 1H), 2.79 (s, 1H), 2.27 (s, 1H), 2.17-2.15 (m, 1H), 2.02 (s, 3H), 1.88-1.85 (m, 1H), 1.67 (s, 2H), 0.86-0.82 (m, 2H), 0.43-0.35 (m, 4H).

Molecular formula: C ₂₁ H ₂₄ N ₄ O Exact molecular weight: 348.20 LC-MS (Pos, m/z ) =349.36[M+H] ⁺ .

Example 35: Synthesis of ( R )-5- _ethynyl - 2-(4- methyl -6-((1-( methyl - d3 ) piperidin -3 - yl ) amino ) piperidin - 3- yl ) phenol ( Compound 84) :

Step 1: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine

( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylphthalimide-3-yl)amino)piperidine-1-carboxylate (0.80 g, 1.71 mmol, 1.0 eq) was dissolved in DCM (8 mL), cooled to 0°C, and then 2,6-lutidine (1.47 g, 13.72 mmol, 8.0 eq) and TMSOTf (1.52 g, 6.86 mmol, 4.0 eq) were added in sequence. The mixture was stirred for 5 min. TLC showed that the reaction was complete. The mixture was quenched by adding water (5 mL), extracted with DCM (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (DCM:MeOH=100:1~10:1) to obtain the product (912.2 mg crude product).

Step 2: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (1-(methyl- d3 )piperidin-3-yl)thiazol-3 _- amine

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (400.0 mg crude, 0.75 mmol, 1.0 eq) was dissolved in DCM (3 mL), deuterated iodomethane (317.0 mg, 3.77 mmol, 5.0 eq) was added, and the reaction was carried out at room temperature for 18 h. The reaction was complete as monitored by TLC, and water (5 mL) was added, and the mixture was extracted with DCM (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (135.9 mg, yield: 47.0%) was obtained by preparative thin layer chromatography (DCM:MeOH=10:1).

Step 3: Synthesis of (R )-5-ethynyl-2-(4-methyl-6-((1-(methyl- d ₃ )piperidin-3-yl)amino)thiazol-3-yl)phenol

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (1-(methyl- d3 )piperidin- ₃ -yl)pyrimidine-3-amine (135.9 mg, 0.35 mmol) was dissolved in DCM (1 mL), and a 4 mol/L hydrogen chloride solution in 1,4-dioxane (1 mL) was added dropwise and reacted at room temperature for 5 min. The reaction was complete as monitored by TLC, and water (1 mL) was added to quench the reaction. The pH was adjusted to 8 with saturated NaHCO ₃ solution, and the mixture was extracted with DCM (2 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (67.1 mg, yield: 58.2%) was obtained by purification by preparative thin layer chromatography (DCM:MeOH =10:1).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.14 (s, 1H), 7.18-7.16 (m, 1H), 7.02-6.98 (m, 2H), 6.75 (d, J =7.2 Hz, 1H), 6.70 (s, 1H), 4.19 (s, 1H), 4.12 (s, 1H), 3.05 (s, 1H), 2.75 (s, 1H), 2.28-2.18(m, 2H), 2.02(s, 3H), 1.86(s, 1H), 1.78-1.77(m, 1H), 1.63-1.60(m, 1H), 1.38(m, 1H).

Molecular formula: C ₁₉ H ₁₉ D ₃ N ₄ O Exact molecular weight: 325.20 LC-MS (Pos, m/z ) =326.33[M+H] ⁺ .

Example 36: Synthesis of ( R )-2-(6-((1- ethylpiperidin -3- yl ) amino )-4- methylpiperidin - 3- yl )-5- ethynylphenol ( Compound 89)

Step 1: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-5-methylpiperidin-3-amine

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (400.0 mg crude, 0.75 mmol, 1.0 eq) was dissolved in DCM (3 mL), iodoethane (587.3 mg, 3.77 mmol, 5.0 eq) was added, and the reaction was carried out at room temperature for 18 h. The reaction was complete as monitored by TLC, and water (5 mL) was added, and the mixture was extracted with DCM (5 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (76.7 mg, yield: 25.8%) was obtained by preparative thin layer chromatography (DCM:MeOH=10:1).

Step 2: Synthesis of (R )-2-(6-((1-ethylpiperidin-3-yl)amino)-4-methylpiperidin-3-yl)-5-ethynylphenol

( R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-5-methylpyridin-3-amine (76.7 mg, 0.19 mmol) was dissolved in DCM (0.5 mL), and a 4 mol/L hydrogen chloride solution in 1,4-dioxane (0.5 mL) was added dropwise and reacted at room temperature for 5 min. The reaction was complete as monitored by TLC, and water (0.5 mL) was added to quench the reaction. The pH was adjusted to 8 with saturated NaHCO ₃ solution, and the mixture was extracted with DCM (1 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (29.7 mg, yield: 45.4%) was purified by preparative thin layer chromatography (DCM:MeOH =10:1).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.12 (s, 1H), 7.18-7.16 (m, 1H), 7.02-6.99 (m, 2H), 6.70 (m, 2H), 4.19 (m, 2H), 2.90-2.70 (m, 6H), 2.03 (s, 3H), 1.96-1.92 (m, 1H), 1.87-1.82 (m, 1H), 1.66 (s, 1H), 1.41 (s, 1H), 1.10-1.09 (m, 3H).

Molecular formula: C ₂₀ H ₂₄ N ₄ O Exact molecular weight: 336.20 LC-MS (Pos, m/z ) = 337.32 [M + H] ⁺ .

Example 37: Synthesis of ( R )-3-(3-((6-(2- hydroxy -4-( prop -1- yn -1- yl ) phenyl )-5- methylpyridin -3- yl ) amino ) piperidin - 1- yl ) propionitrile ( Compound 78)

Step 1: Synthesis of (R )-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)propionitrile

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (250 mg, 0.657 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (333 mg, 3.29 mmol, 5.0 eq) and 3-bromopropionitrile (441 mg, 3.29 mmol, 5.0 eq) were added, and stirred at room temperature for 20 h. The product was concentrated and purified by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (263 mg, yield: 92.3%).

Step 3: Synthesis of (R )-3-(3-((6-(2-hydroxy-4-(prop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)piperidin-1-yl)propionitrile

( R )-3-(3-((6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methylphthalimide-3-yl)amino)piperidin-1-yl)propionitrile (260 mg, 0.600 mmol, 1.0 eq) was dissolved in DCM (4 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.45 mL, 1.80 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, extracted with DCM (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (166 mg, yield: 73.7%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.01 (s, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.96-6.89 (m, 2H), 6.66 (s, 1H), 6.57 (d, J = 8.0 Hz, 1H), 4.03-4.01 (m, 1H), 3.02 (d, J = 8.2 Hz, 1H), 2.73 (d, J = 10.8 Hz, 1H), 2.69-2.66 (m, 2H), 2.64-2.60 (m, 2H), 2.11-1.96 (m, 8H), 1.89-1.86 (m, 1H), 1.73-1.70 (m, 1H), 1.58-1.49 (m, 1H), 1.34-1.24 (m, 1H).

Molecular formula: C ₂₂ H ₂₅ N ₅ O Exact molecular weight: 375.21 LC-MS (Pos, m/z ) = 376.19 [M + H] ⁺ .

Example 38: Synthesis of ( R )-2-(4- methyl -6-((1-(2,2,2- trifluoroethyl ) piperidin -3 - yl ) amino ) piperidin - 3- yl )-5-( prop -1- yn -1- yl ) phenol ( Compound 79)

Step 1: Synthesis of 2,2,2-trifluoroethyl-4-methylbenzenesulfonate

Dissolve 2,2,2-trifluoroethanol (5.00 g, 50.0 mmol, 1.0 eq) in DCM (100 mL), add triethylamine (7.59 g, 75.0 mmol, 1.5 eq) and 4-methylbenzenesulfonyl chloride (9.53 g, 50.0 mmol, 1.0 eq), and stir at room temperature for 20 h. Wash the reaction solution with water (50 mL×3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify it by silica gel column chromatography (PE:EA=10:1) to obtain the product (11.9 g, yield: 93.7%).

Step 2: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridin-3-amine

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (piperidin-3-yl)pyrimidine-3-amine (250 mg, 0.657 mmol, 1.0 eq) was dissolved in DMF (5 mL), 2,2,2-trifluoroethyl-4-methylbenzenesulfonate (334 mg, 1.31 mmol, 2.0 eq) and _K2CO3 (181 mg, 1.31 mmol, 2.0 eq) were added, the _mixture was heated to 100°C and reacted for 48 h. Add water (30 mL) to quench, extract with EA (30 mL), wash the organic phase with saturated brine (20 mL×3), dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (DCM:MeOH=100:1~50:1) to obtain the product (148 mg, yield: 48.7%).

Step 3: Synthesis of (R )-2-(4-methyl-6-((1-(2,2,2-trifluoroethyl)piperidin-3-yl)amino)piperidin-3-yl)-5-(prop-1-yn-1-yl)phenol

( R )-6-(2-(ethoxymethoxy)-4-(prop-1-yn-1-yl)phenyl)-5-methyl- N- (1-(2,2,2-trifluoroethyl)piperidin-3-yl)pyridin-3-amine (148 mg, 0.320 mmol, 1.0 eq) was dissolved in DCM (2 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.24 mL, 0.960 mmol, 3.0 eq) was added dropwise and stirred at room temperature for 2 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, extracted with DCM (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=100:1~50:1) to obtain the product (67.0 mg, yield: 51.8%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.01 (s, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.9 Hz, 2H), 6.66 (s, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.04-4.01 (m, 1H), 3.25-3.15 (m, 3H), 2.83 (d, J = 10.8 Hz, 1H), 2.40-2.35 (m, 1H), 2.26-2.21 (m, 1H), 2.05 (s, 3H), 2.03 (s, 3H), 1.90 (d, J = 8.8 Hz, 1H), 1.71 (d, J = 13.2 Hz, 1H), 1.60-1.55 (m, 1H), 1.31-1.24 (m, 1H).

Molecular formula: C ₂₁ H ₂₃ F ₃ N ₄ O Exact molecular weight: 404.18 LC-MS (Pos, m/z ) = 405.22 [M + H] ⁺ .

Example 39: Synthesis of ( R )-2-(3-((1- cyclopropylpiperidin -3 -yl ) amino )-5- methyl -1,2,4- trioxan - 6- yl )-5- ethynylphenol ( Compound 96)

Step 1: Synthesis of 5-methyl-3-(methylsulfinyl)-1,2,4-triazine

Dissolve 5-methyl-3-methylthio-1,2,4-triazine (70.0 g, 0.496 mol, 1.0 eq) in DCM (700 mL), stir at room temperature, add m-chloroperbenzoic acid (101 g, 0.496 mol, 1.0 eq) in batches, stir at room temperature for 1 h. Filter, reduce the pressure and concentrate the filtrate, and directly put it into the next step.

Step 2: Synthesis of (R )-3-((5-methyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

The crude 5-methyl-3-(methylsulfinyl)-1,2,4-trioxane obtained in the previous step was dissolved in 1,4-dioxane (200 mL), triethylamine (100 g, 0.992 mol, 2.0 eq) and ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (99.3 g, 0.496 mol, 1.0 eq) were added, and the mixture was heated to 100°C for 1 h. Cool to room temperature, add water (600 mL) to quench, extract with EA (300 mL×2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (PE:EA=10:1~1:1) to obtain the product (82.5 g, two-step yield: 56.7%).

Step 3: Synthesis of (R )-3-((6-bromo-5-methyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Dissolve ( R )-3-((5-methyl-1,2,4-trithiocarbamate-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (12.0 g, 40.9 mmol, 1.0 eq) in DMF (100 mL), stir at room temperature, and then add NBS (7.28 g, 40.9 mmol, 1.0 eq) in batches. React at room temperature for 4 hours. Add water (300 mL) to quench, extract with EA (200 mL), wash the organic phase with water (100 mL×3), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (PE:EA=20:1~2:1) to obtain the product (6.30 g, yield: 41.4%).

Step 4: Synthesis of (R )-6-bromo-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine

( R )-3-((6-bromo-5-methyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (6.30 g, 16.9 mmol, 1.0 eq) was dissolved in DCM (15 mL), TFA (15 mL) was added dropwise, and the reaction was carried out at room temperature for 2 h. The pH value was adjusted to 8 with a saturated aqueous _NaHCO3 solution, and the mixture was extracted with a mixed solvent of DCM:MeOH = 10:1 (40 mL×5). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (DCM:MeOH = 50:1~10:1) to obtain the product (4.10 g, yield: 89.0%).

Step 5: Synthesis of (R )-6-bromo- N- (1-cyclopropylpiperidin-3-yl)-5-methyl-1,2,4-trioxan-3-amine

Dissolve ( R )-6-bromo-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (300 mg, 1.10 mmol, 1.0 eq) in MeOH (20 mL), add (1-ethoxycyclopropoxy)trimethylsilane (767 mg, 4.40 mmol, 4.0 eq) and CsF (334 mg, 2.20 mmol, 2.0 eq), heat to 50°C, stir for 1 h, add _NaBH3CN (276 mg, 4.40 mmol, 4.0 eq), and react for 0.5 h. Cool to room temperature, concentrate, add saturated NaHCO ₃ aqueous solution, extract with EA (20 mL×2), dry the organic phase over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (308 mg, yield: 89.5%).

Step 6: Synthesis of (R )-4-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde

3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (230 mg, 0.751 mmol, 1.3eq), ( R )-6-bromo- N- (1-cyclopropylpiperidin-3-yl)-5-methyl-1,2,4-trioxan-3-amine (180 mg, 0.577 mmol, 1.0eq), Pd( _PPh3 ) ₄ (42.2 mg, 0.0577 mmol, 0.1eq) and _NaHCO3 (96.9 mg, 1.15 mmol, 2.0eq) were added to 1,4-dioxane (6 mL) in sequence, _H2O (3 mL) was added, and the mixture was heated to 80℃ under nitrogen protection for 24 h. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with EA (20 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (112 mg, yield: 49.7%).

Step 7: Synthesis of (R ) -N- (1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trioxan-3-amine

( R )-4-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-trioxan-6-yl)-3-(ethoxymethoxy)benzaldehyde (112 mg, 0.272 mmol, 1.0 eq) was dissolved in MeOH (4 mL), _K2CO3 ( _75.2 mg, 0.544 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (78.4 mg, 0.408 mmol, 1.5 eq) were added, and the mixture was stirred at room temperature for 1 h. Water (20 mL) was added, and the mixture was extracted with EA (15 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (102 mg, yield: 92.0%) was obtained by silica gel column chromatography (DCM:MeOH=100:1~20:1).

Step 8: Synthesis of (R )-2-(3-((1-cyclopropylpiperidin-3-yl)amino)-5-methyl-1,2,4-trioxan-6-yl)-5-ethynylphenol

( R ) -N- (1-cyclopropylpiperidin-3-yl)-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trioxane-3-amine (102 mg, 0.250 mmol, 1.0 eq) was dissolved in DCM (3 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.25 mL, 1.00 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, extracted with DCM (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=100:1~20:1) to obtain the product (68.5 mg, yield: 78.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.09 (s, 1H), 7.40 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 2H), 4.22 (s, 1H), 3.91 (s, 1H), 3.07 (d, J = 7.0 Hz, 1H), 2.81 (d, J = 10.5 Hz, 1H), 2.18-2.10 (m, 5H), 1.86 (d, J = 8.4 Hz, 1H), 1.69-1.63 (m, 2H), 1.50-1.34 (m, 2H), 0.41 (d, J = 6.1 Hz, 2H), 0.31 (s, 2H).

Molecular formula: C ₂₀ H ₂₃ N ₅ O Exact molecular weight: 349.19 LC-MS (Pos, m/z ) = 350.22 [M + H] ⁺ .

Example 40: Synthesis of ( R )-2-(3-((1- ethylpiperidin -3- yl ) amino )-5- methyl -1,2,4 -trioxan - 6- yl )-5- ethynylphenol ( Compound 91)

Step 1: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-methylphenyl)-5-methyl-1,2,4-triazine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.68 g, 8.75 mmol, 1.3 eq), ( R )-3-((6-bromo-5-methyl-1,2,4-trioxaborolan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.50 g, 6.72 mmol, 1.0 eq), Pd(dppf) _Cl2 (492 mg, 0.672 mmol, 0.1 eq) and _K2CO3 (1.86 g, 13.4 mmol, 2.0 eq) were added to 1,4-dioxane (40 mL) in sequence, _H2O (20 mL) was _added , and the mixture was heated to 110℃ under nitrogen protection for 2 h. Cool to room temperature, add water (50 mL), extract with EA (50 mL×3), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (PE:EA=10:1~2:1) to obtain the product (2.62 g, yield: 82.7%).

Step 2: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Dissolve ( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methyl-1,2,4-trioxan-3-yl)amino)piperidine-1-carboxylate (2.62 g, 5.56 mmol, 1.0 eq) in MeOH (30 mL), add _K2CO3 (1.54 g, 11.1 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.60 g, 8.34 mmol, 1.5 eq), and stir at room temperature _for 1 h. Concentrate, add water (50 mL), extract with EA (50 mL×2), dry the organic phase with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by silica gel column chromatography (PE:EA=10:1~2:1) to obtain the product (2.34 g, yield: 90.1%).

Step 3: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine

Dissolve ( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trithion-3-yl)amino)piperidine-1-carboxylate (2.34 g, 5.00 mmol, 1.0 eq) in DCM (40 mL), then add 2,6-lutidine (4.29 g, 40.0 mmol, 8.0 eq), cool to 0°C in an ice-water bath, and then add TMSOTf (4.45 g, 20.0 mmol, 4.0 eq) dropwise. After the addition was completed, the mixture was quenched with water (50 mL) and separated. The aqueous phase was extracted with DCM (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (1.30 g, yield: 70.7%).

Step 4: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-5-methyl-1,2,4-triazine-3-amine

( R )-6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (250 mg, 0.680 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (344 mg, 3.40 mmol, 5.0 eq) and iodoethane (530 mg, 3.40 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 16 h. Water was added, and the mixture was extracted with DCM (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (212 mg, yield: 78.8%) was obtained by silica gel column chromatography (DCM:MeOH=50:1~10:1).

Step 5: Synthesis of (R )-2-(3-((1-ethylpiperidin-3-yl)amino)-5-methyl-1,2,4-trioxan-6-yl)-5-ethynylphenol

( R )-6-(2-(Ethoxymethoxy)-4-ethynylphenyl) -N- (1-ethylpiperidin-3-yl)-5-methyl-1,2,4-trioxane-3-amine (200 mg, 0.506 mmol, 1.0 eq) was dissolved in DCM (3 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.51 mL, 2.02 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with saturated NaHCO ₃ aqueous solution, extracted with DCM (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (102 mg, yield: 59.8%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.17 (s, 1H), 7.60 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.04 (d, J = 6.8 Hz, 2H), 4.23 (s, 1H), 4.10 (m, 1H), 3.18 (s, 1H), 2.93 (s, 1H), 2.67-2.60 (m, 2H), 2.19 (s, 4H), 1.91 (d, J = 4.9 Hz, 1H), 1.78 (s, 1H), 1.63 (s, 1H), 1.44 (s, 1H), 1.08 (s, 3H).

Molecular formula: C ₁₉ H ₂₃ N ₅ O Exact molecular weight: 337.19 LC-MS (Pos, m/z ) = 338.22 [M + H] ⁺ .

Example 41: Synthesis of ( R )-5- ethynyl -2-(3-((1-(2- hydroxyethyl ) piperidin -3- yl ) amino )-5- methyl -1,2,4 -trioxan - 6- yl ) phenol ( Compound 99)

Step 1: Synthesis of (R )-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trioxan-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (250 mg, 0.680 mmol, 1.0 eq) was dissolved in DCM (5 mL), triethylamine (344 mg, 3.40 mmol, 5.0 eq) and 2-bromoethanol (425 mg, 3.40 mmol, 5.0 eq) were added, and the mixture was stirred at room temperature for 30 h. Water was added, and the mixture was extracted with DCM (30 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (178 mg, yield: 63.6%).

Step 2: Synthesis of (R )-5-ethynyl-2-(3-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-5-methyl-1,2,4-trioxan-6-yl)phenol

( R )-2-(3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl-1,2,4-trioxan-3-yl)amino)piperidin-1-yl)ethan-1-ol (178 mg, 0.433 mmol, 1.0 eq) was dissolved in DCM (3 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.43 mL, 1.73 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, extracted with DCM (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (102 mg, yield: 66.7%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 10.22 (s, 1H), 7.72 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.07-7.03 (m, 2H), 4.25 (s, 1H), 4.91 (s, 1H), 4.23 (s, 2H), 3.64 (s, 2H), 2.85 (s, 3H), 2.20 (s, 3H), 1.89-1.71 (m, 3H), 1.50 (s, 1H), 0.96-0.82 (m, 1H).

Molecular formula: C ₁₉ H ₂₃ N ₅ O ₂ Exact molecular weight: 353.19 LC-MS (Pos, m/z ) = 354.28 [M + H] ⁺ .

Example 42: Synthesis of ( R )-5- ethynyl -2-(5- methyl -3-((1-( methyl _- d3 ) piperidin -3 -yl ) amino )-1,2,4 -trioxan - 6- yl ) phenol ( Compound 86)

Step 1: Synthesis of (R )-6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (1-(methyl- d3 )piperidin-3-yl)-1,2,4-trioxan- ₃ -amine

( R )-6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (piperidin-3-yl)-1,2,4-trioxan-3-amine (450 mg, 1.22 mmol, 1.0 eq) was dissolved in DCM (20 mL), triethylamine (370 mg, 3.66 mmol, 3.0 eq) and deuterated iodomethane (530 mg, 3.66 mmol, 3.0 eq) were added, and the mixture was stirred at room temperature for 2 h. Water was added, the mixture was separated, the aqueous phase was extracted with DCM (20 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (192 mg, yield: 40.8%).

Step 2: Synthesis of (R )-5 _- ethynyl-2-(5-methyl-3-((1-(methyl- d3 )piperidin-3-yl)amino)-1,2,4-trioxan-6-yl)phenol

( R )-6-(2-(Ethoxymethoxy)-4-ethynylphenyl)-5-methyl- N- (1-(methyl- d3 )piperidin- ₃ -yl)-1,2,4-trioxan-3-amine (192 mg, 0.499 mmol, 1.0 eq) was dissolved in DCM (3 mL), and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 0.50 mL, 2.00 mmol, 4.0 eq) was added dropwise and stirred at room temperature for 1 h. The pH value was adjusted to 8 with a saturated NaHCO ₃ aqueous solution, extracted with DCM (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (DCM:MeOH=50:1~10:1) to obtain the product (108 mg, yield: 66.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.10 (s, 1H), 7.45 (s, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.04-7.02 (m, 2H), 4.22 (s, 1H), 3.99 (s, 1H), 2.87 (s, 1H), 2.63 (d, J = 10.8 Hz, 1H), 2.18 (s, 3H), 1.90-1.84 (m, 3H), 1.72-1.68 (m, 1H), 1.58-1.49 (m, 1H), 1.35-1.29 (m, 1H).

Molecular formula: C ₁₈ H ₁₈ D ₃ N ₅ O Exact molecular weight: 326.19 LC-MS (Pos, m/z ) = 327.24 [M + H] ⁺ .

Example 43: Synthesis of 2-(4 -difluoromethyl -6-((( cis )-3- hydroxy -3- methylcyclobutyl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 102)

Step 1: Synthesis of intermediate 3,6-dichloro-4-difluoromethylindole

Dissolve 3,6-dichlorothiazolium (30.0 g, 148.98 mmol, 1.0 eq) in water (800 mL), add difluoroacetic acid (38.6 g, 402 mmol, 2.0 eq) and silver nitrate (34.2 g, 201 mmol, 1.0 eq), add concentrated sulfuric acid (33 mL, 603 mmol, 3.0 eq) to the reaction solution at 50°C, raise the temperature to 60°C, and add an aqueous solution (400 mL) of ammonium persulfate (137.6 g, 603 mmol, 3.0 eq) to the reaction solution. After the addition is complete, raise the temperature to 70°C and react for 5 min. The reaction solution was adjusted to pH 8 with 15% sodium hydroxide aqueous solution, extracted with ethyl acetate (500 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the product (8.98 g, yield: 22.5 %).

Step 2: Synthesis of the intermediate ( cis )-3-((6-chloro-5-difluoromethylindole-3-yl)amino)-1-methylcyclobutyl-1-ol

3,6-Dichloro-4-difluoromethylthiazolium (3.3 g, 16.58 mmol, 1.0 eq) was dissolved in n-butanol (33 mL), (cis )-3-amino-1-methylcyclobutyl-1-ol hydrochloride (4.56 g, 33.16 mmol, 2.0 eq) and N , N -diisopropylethylamine (8.57 g, 66.32 mmol, 4.0 eq) were added, and the mixture was reacted at 120 °C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, water (50 mL) was added, and dichloromethane (50 mL×10) was used for extraction. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1~1:1) to obtain the product (1.35 g, yield: 30.9 %).

Step 3: Synthesis of the intermediate 4-(4-difluoromethyl-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)benzaldehyde

( cis )-3-((6-chloro-5-difluoromethylbenzyl)amino)-1-methylcyclobutyl-1-ol (200 mg, 0.759 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (349 mg, 1.139 mmol, 1.5 eq), potassium carbonate (210 mg, 1.518 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (88 mg, 0.0759 mmol, 0.1 eq) and water (0.5 mL) were added thereto. The temperature was raised to 90°C under nitrogen protection for 6 h. The reaction was complete as determined by TLC. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (20 mL), the filtrate was dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1~1:2) to obtain the product (178 mg, yield: 57.6 %).

Step 4: Synthesis of the intermediate ( cis )-3-((5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)pyrimidine-3-yl)amino)-1-methylcyclobutyl-1-ol

4-(4-Difluoromethyl-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde (178 mg, 0.437 mmol, 1.0 eq) was dissolved in methanol (3 mL). Potassium carbonate (121 mg, 0.874 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (126 mg, 0.656 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25 °C for 2 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL×2). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain the product (117 mg, yield: 66.5 %).

Step 5: Synthesis of compound 2-(4-difluoromethyl-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)thiazol-3-yl)-5-ethynylphenol

( cis )-3-((5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)phthalimide-3-yl)amino)-1-methylcyclobutyl-1-ol (117 mg, 0.29 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 10 min. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate = 1:2) to obtain the product (37 mg, yield: 37.0 %).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.24 (s, 1H), 7.49-7.48 (d, 1H), 7.27-7.25 (d, 1H), 7.04-7.00 (m, 3H), 6.77 (t, J=54.6 Hz, 1H), 5.06 (s, 1H), 4.32 (s, 1H), 4.06-3.98 (m, 1H), 2.47-2.42 (m, 2H), 1.99-1.95 (m, 2H), 1.30 (s, 3H).

Molecular formula: C ₁₈ H ₁₇ F ₂ N ₃ O ₂ Exact molecular weight: 345.13 LC-MS ( m / z ): 346.15 [M+H] ⁺ .

Example 44: Synthesis of 2-(4,5- bis ( difluoromethyl )-6-((( cis )-3- hydroxy -3- methylcyclobutyl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 110)

Step 1: Synthesis of the intermediate 3,6-dichloro-4,5-bis(difluoromethyl)pyrimidine

Dissolve 3,6-dichlorothiazolium (30.0 g, 148.98 mmol, 1.0 eq) in water (800 mL), add difluoroacetic acid (38.6 g, 402 mmol, 2.0 eq) and silver nitrate (34.2 g, 201 mmol, 1.0 eq), add concentrated sulfuric acid (33 mL, 603 mmol, 3.0 eq) to the reaction solution at 50°C, raise the temperature to 60°C, and add an aqueous solution (400 mL) of ammonium persulfate (137.6 g, 603 mmol, 3.0 eq) to the reaction solution. After the addition is complete, raise the temperature to 70°C and react for 5 min. The pH value was adjusted to 8 with 15% aqueous sodium hydroxide solution, extracted with ethyl acetate (500 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain the product (9.15 g, yield: 18.3 %).

Step 2: Synthesis of the intermediate ( cis )-3-((6-chloro-4,5-bis(difluoromethyl)pyrimidine-3-yl)amino)-1-methylcyclobutyl-1-ol

3,6-Dichloro-4,5-bis(difluoromethyl)phthalimide (2.5 g, 10.04 mmol, 1.0 eq) was dissolved in n-butanol (20 mL), and ( cis )-3-amino-1-methylcyclobutyl-1-ol hydrochloride (2.76 g, 20.08 mmol, 2.0 eq) and N , N -diisopropylethylamine (5.19 g, 40.16 mmol, 4.0 eq) were added thereto. The mixture was reacted at 120°C for 0.5 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1~2:1) to obtain the product (232 mg, yield: 7.3 %).

Step 3: Synthesis of the intermediate 4-(4,5-bis(difluoromethyl)-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)benzaldehyde

Dissolve ( cis )-3-((6-chloro-4,5-bis(difluoromethyl)pyrimidine-3-yl)amino)-1-methylcyclobutyl-1-ol (212 mg, 0.676 mmol, 1.0 eq) in 1,4-dioxane (2 mL), add 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (310 mg, 1.014 mmol, 1.5 eq), potassium carbonate (187 mg, 1.352 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (78 mg, 0.0676 mmol, 0.1 eq) and water (0.5 mL), and heat to 90°C under nitrogen for 1 h. h, TLC detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filter cake was washed with dichloromethane (10 mL), the filtrate was dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain the product (188 mg, yield: 60.8 %).

Step 4: Synthesis of the intermediate ( cis )-3-((4,5-bis(difluoromethyl)-6-(2-ethoxymethoxy-4-ethynylphenyl)pyrimidine-3-yl)amino)-1-methylcyclobutyl-1-ol

4-(4,5-Bis(difluoromethyl)-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde (188 mg, 0.41 mmol, 1.0 eq) was dissolved in methanol (2 mL). Potassium carbonate (113 mg, 0.82 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (119 mg, 0.62 mmol, 1.5 eq) were added sequentially. The mixture was reacted at 25°C for 3 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, water (5 mL) was added to the concentrated solution, and the mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain the product (100 mg, yield: 53.8 %).

Step 5: Synthesis of compound 2-(4,5-bis(difluoromethyl)-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)thiazol-3-yl)-5-ethynylphenol

( cis )-3-((4,5-bis(difluoromethyl)-6-(2-ethoxymethoxy-4-ethynylphenyl)phthalimino)-1-methylcyclobutyl-1-ol (100 mg, 0.22 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 5 min. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the product (24 mg, yield: 27.6%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.32 (s, 1H), 7.56-7.30 (m, 2H), 7.07-7.02 (t, 2H), 6.86-6.60 (m, 2H), 5.01 (s, 1H), 4.26-4.21 (m, 2H), 2.47-2.45 (m, 2H), 2.16-2.11 (m, 2H), 1.30 (s, 3H).

Molecular formula: C ₁₉ H ₁₇ F ₄ N ₃ O ₂ Exact molecular weight: 395.13 LC-MS ( m / z ): 396.13 [M+H] ⁺ .

Example 45: Synthesis of ( R )-6-(4- ethynyl -2- hydroxyphenyl )-5- methyl -3-((1- methylpiperidin -3- yl ) amino ) thiazol - 4- carbonitrile ( Compound 103)

Step 1: Synthesis of intermediate 3,6-dichloroindole-4-carboxylic acid chloride

Dissolve 3,6-dichlorothiazol-4-carboxylic acid (24.07 g, 124.7 mmol, 1.0 eq) in dichloromethane (240 mL), add N , N -dimethylformamide (0.05 mL) dropwise, slowly add oxalyl chloride (47.48 g, 374.1 mmol, 3.0 eq) dropwise at 0°C, react at 25°C for 2 h, and the reaction is complete as determined by TLC. Concentrate the reaction solution, and use the crude product directly in the next step.

Step 2: Synthesis of intermediate 3,6-dichlorobenzamide-4-carboxamide

Dissolve 3,6-dichlorothiazol-4-carboxylic acid chloride (crude, 124.7 mmol, 1.0 eq) in acetonitrile (250 mL) and drop it into aqueous ammonia (350 g, 2494 mmol, 10.0 eq) at 0°C. After the addition is complete, TLC indicates that the reaction is complete. Extract with ethyl acetate (300 mL×4), combine the organic phases, dry with anhydrous sodium sulfate, and concentrate to obtain the product (22.94 g, yield: 95.8 %).

Step 3: Synthesis of intermediate 3,6-dichloroindole-4-carbonitrile

Dissolve 3,6-dichlorothiazol-4-carboxamide (22.94 g, 119.5 mmol, 1.0 eq) in dichloromethane (230 mL). Add triethylamine (48.37 g, 478.0 mmol, 4.0 eq) and trifluoroacetic anhydride (50.2 g, 239.0 mmol, 2.0 eq) in turn at 0°C. After the addition is complete, react at 0°C for 1 h, then raise the temperature to 25°C for 1 h. The reaction is complete as determined by TLC. The reaction solution was poured into a saturated sodium bicarbonate aqueous solution (200 mL), extracted with dichloromethane (200 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the product (15.86 g, yield: 76.3 %).

Step 4: Synthesis of intermediate 3,6-dichloro-5-methylindole-4-carbonitrile

Dissolve 3,6-dichlorothiazol-4-carbonitrile (4.69 g, 26.96 mmol, 1.0 eq) in water (150 mL), add acetic acid (4.86 g, 80.88 mmol, 3.0 eq) and silver nitrate (4.58 g, 26.96 mmol, 1.0 eq), add concentrated sulfuric acid (4.3 mL, 80.88 mmol, 3.0 eq) to the reaction solution at 50°C, raise the temperature to 60°C, add an aqueous solution (50 mL) of ammonium persulfate (18.46 g, 80.88 mmol, 3.0 eq) to the reaction solution, react at 70°C for 10 min, and the reaction is complete by TLC. The pH value was adjusted to 8 with 15% sodium hydroxide aqueous solution, extracted with ethyl acetate (300 mL×3), the organic phases were combined, dried, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain the product (2.8 g, yield: 55.3 %).

Step 5: Synthesis of (R )-3-((6-chloro-4-cyano-5-methylphthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-5-methylthiazol-4-carbonitrile (1.4 g, 7.45 mmol, 1.0 eq) was dissolved in N , N -dimethylacetamide (10 mL), and ( R )-1-tert-butyloxycarbonyl-3-aminopiperidine (2.98 g, 14.9 mmol, 2.0 eq) and N , N -diisopropylethylamine (1.93 g, 14.9 mmol, 2.0 eq) were added thereto. The mixture was reacted at 120℃ for 0.5 h. The reaction was almost complete as determined by TLC. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=10:1~4:1) to obtain the product (714 mg, yield: 27.3 %).

Step 6: Synthesis of intermediate ( R )-6-chloro-5-methyl-3-(piperidin-3-ylamino)phthalimide-4-carbonitrile

Dissolve ( R )-3-((6-chloro-4-cyano-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (714 mg, 2.03 mmol) in dichloromethane (10 mL), drop it into trifluoroacetic acid (10 mL), react at 25°C for 5 min, and the reaction is complete by TLC detection. Concentrate the reaction solution, dissolve the reaction solution in dichloromethane (10 mL), pour into saturated sodium bicarbonate aqueous solution (20 mL), separate the liquids, extract the aqueous phase with a mixed solvent of dichloromethane:methanol = 5:1 (10 mL×10), combine the organic phases, dry over anhydrous magnesium sulfate, concentrate to obtain a crude product, and directly use it in the next step.

Step 7: Synthesis of intermediate ( R )-6-chloro-5-methyl-3-((1-methylpiperidin-3-yl)amino)indole-4-carbonitrile

( R )-6-Chloro-5-methyl-3-(piperidin-3-ylamino)phthalimide-4-carbonitrile (crude, 2.03 mmol, 1.0 eq) was dissolved in methanol (5 mL). A 37% aqueous formaldehyde solution (165 mg, 2.03 mmol, 1.0 eq) was added and the mixture was reacted at 25°C for 2 h. Sodium cyanoborohydride (140 mg, 2.23 mmol, 1.1 eq) was added and the mixture was reacted at 25°C for 5 min. The reaction was complete as determined by TLC. The reaction solution was concentrated, and a saturated sodium bicarbonate aqueous solution (5 mL) was added to the concentrated solution. The mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~10:1) to obtain the product (402 mg, two-step yield: 74.6%).

Step 8: Synthesis of the intermediate ( R )-6-(2-ethoxymethoxy-4-methylphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)thiazol-4-carbonitrile

( R )-6-chloro-5-methyl-3-((1-methylpiperidin-3-yl)amino)pyridine-4-carbonitrile (172 mg, 0.645 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (238 mg, 0.774 mmol, 1.2 eq), an aqueous solution (0.5 mL) of potassium carbonate (178 mg, 1.29 mmol, 2.0 eq) and Pd( _PPh3 ) ₄ (75 mg, 0.0645 mmol, 0.1 eq) were added in sequence. The temperature was raised to 90°C under nitrogen protection for reaction for 3 hours. h, TLC detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~50:1) to obtain the product (121 mg, yield: 45.8%).

Step 9: Synthesis of the intermediate ( R )-6-(2-ethoxymethoxy-4-ethynylphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)thiazol-4-carbonitrile

( R )-6-(2-ethoxymethoxy-4-formylphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)tantalum-4-carbonitrile (121 mg, 0.295 mmol, 1.0 eq) was dissolved in methanol (2 mL), potassium carbonate (82 mg, 0.59 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (85 mg, 0.443 mmol, 1.5 eq) were added sequentially, and the mixture was reacted at 25°C for 3 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, water (5 mL) was added thereto, and the mixture was extracted with dichloromethane (5 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 7:1) to obtain the product (40 mg, yield: 33.3 %).

Step 10: Synthesis of compound ( R )-6-(4-ethynyl-2-hydroxyphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)thiazol-4-carbonitrile

( R )-6-(2-ethoxymethoxy-4-ethynylphenyl)-5-methyl-3-((1-methylpiperidin-3-yl)amino)thiazol-4-carbonitrile (40 mg, 0.0986 mmol) was dissolved in dichloromethane (1 mL) and slowly added dropwise into trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 5 min. The reaction was complete as determined by TLC. The reaction solution was concentrated, and dichloromethane (5 mL) was added to the concentrated solution. The pH value was adjusted to alkaline with saturated sodium bicarbonate aqueous solution, and extracted with a mixed solvent of dichloromethane:methanol = 10:1 (10 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by preparative thin layer chromatography (dichloromethane:methanol = 7:1) to obtain the product (9 mg, yield: 26.5%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.16 (s, 1H), 7.23-7.21 (t, 1H), 7.05-6.95 (m, 2H), 6.90 (s, 1H), 4.42 (s, 1H), 4.24 (s, 1H), 3.35 (s, 3H), 3.12-3.05 (m, 1H), 2.78-2.74 (m, 1H), 2.40-2.34 (m, 2H), 2.24 (s, 3H), 1.91-1.85 (m, 2H), 1.62-1.54 (m, 2H).

Molecular formula: C ₂₀ H ₂₁ N ₅ O Exact molecular weight: 347.17 LC-MS ( m / z ): 348.21 [M+H] ⁺ .

Example 46: Synthesis of ( R )-2-(4- methyl -6-((1- methylpiperidin -3- yl ) amino ) pyrimidine - 3- yl )-5-(3,3,3 -trifluoroprop -1- yn -1- yl ) phenol ( Compound 111)

Step 1: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)-5-methylpiperidin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Togni reagent (749.9 mg, 2.27 mmol, 2.0 eq), CuI (129.8 mg, 0.68 mmol, 0.6 eq), 1,2-phenanthroline (122.8 mg, 0.68 mmol, 0.6 eq) and KHCO ₃ (227.4 mg, 2.27 mmol, 2.0 eq) were added to DCM (10 mL). Under nitrogen protection, ( R )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylphthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (530.0 mg, 1.14 mmol, 1.0 eq) was dissolved in DCM (10 mL) and placed in a syringe at 6 h and then slowly and evenly injected into the above reaction system. After the injection, stir at room temperature overnight. TLC showed that the reaction was complete. Water (15 mL) was added, and the liquid was separated. The aqueous phase was extracted with DCM (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by preparative thin layer chromatography (DCM:MeOH=10:1) to obtain the product (374.6 mg, yield: 61.7%).

Step 2: Synthesis of (R )-2-(4-methyl-6-(piperidin-3-ylamino)pyrimidine-3-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)phenol

Dissolve ( R )-tert-butyl 3-((6-(2-(ethoxymethoxy)-4-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)-5-methylpiperidine-3-yl)amino)piperidine-1-carboxylate (374.6 mg, 0.70 mmol) in DCM (2 mL), add 4 mol/L hydrogen chloride solution in 1,4-dioxane (2 mL) dropwise, and react at room temperature for 1 h. The reaction was complete as monitored by TLC, and water (2 mL) was added. The pH was adjusted to 8 with saturated NaHCO ₃ solution, and the mixture was extracted with a mixed solvent (DCM:MeOH = 10:1) (2 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography (DCM: 7 mol/L ammonia methanol solution = 10:1) to obtain the product (137.5 mg, yield: 52.1%).

Step 3: Synthesis of (R )-2-(4-methyl-6-((1-methylpiperidin-3-yl)amino)pyrimidine-3-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)phenol

( R )-2-(4-methyl-6-(piperidin-3-ylamino)pyrimidine-3-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)phenol (137.5 mg, 0.37 mmol, 1.0 eq) was dissolved in MeOH (2 mL), and aqueous formaldehyde solution (37%, 29.7 mg, 0.37 mmol, 1.0 eq) was added. After stirring for 5 min, sodium cyanoborohydride (23.0 mg, 0.37 mmol, 1.0 eq) was added and the reaction was stirred at room temperature for 1 h. The reaction was complete as monitored by TLC. The solution was concentrated under reduced pressure and saturated sodium bicarbonate solution (5 mL) was added. The solution was extracted with a mixed solvent (DCM:MeOH = 10:1) (2×2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product (67.8 mg, yield: 47.5%) was obtained by preparative thin layer chromatography (DCM: 7 mol/L ammonia methanol solution = 10:1).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.48 (s, 1H), 7.32-7.30 (m, 1H), 7.25-7.23 (m, 1H), 7.19 (s, 1H), 6.78-6.76 (m, 1H), 6.71 (s, 1H), 4.10-4.08 (m, 1H), 3.00-2.99 (m, 1H), 2.69 (s, 1H), 2.30 (s, 3H), 2.20 (s, 1H), 2.02 (m, 4H), 1.87-1.85 (m, 1H), 1.78-1.74 (m, 1H), 1.63-1.55 (m, 1H), 1.36-1.34 (m, 1H).

Molecular formula: C ₂₀ H ₂₁ N ₄ F ₃ O Exact mass: 390.17 LC-MS (Pos, m/z ) =391.37[M+H] ⁺ .

Example 47: Synthesis of ( R )-2-(4- cyclopropyl -6-( piperidin -3 -ylamino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 149)

Step 1: Synthesis of (R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-methylphenyl)pyrimidine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-chloro-5-cyclopropylpyridinium-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.25 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.69 g, 5.52 mmol, 1.3 eq), anhydrous potassium carbonate (1.17 g, 8.50 mmol, 2.0 eq) and Pd(PPh ₃ ) ₄ (491.0 mg, 0.42 mmol, 0.1eq) was added to a mixed solution of 1,4-dioxane (10.0mL) and water (5.0mL), and the reaction was carried out at 100°C for 4h under nitrogen protection. The reaction was completed when monitored by TLC. Ethyl acetate (100.0mL) was added and washed with water (100.0mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~80:1) to obtain the product (2.0g, yield: 94.7%).

Step 2: Synthesis of (R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)pyrimidine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-formylphenyl)phthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 4.02 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (1.16 g, 6.04 mmol, 1.5 eq) and anhydrous potassium carbonate (1.11 g, 8.04 mmol, 2.0 eq) were added to methanol (20.0 mL) and reacted at room temperature for 12 h. The reaction was complete as monitored by TLC. The system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~80:1) to obtain the product (1.5 g, yield: 75.7%).

Step 3: Synthesis of (R )-2-(4-cyclopropyl-6-(piperidin-3-ylamino)thiazol-3-yl)-5-ethynylphenol

( R )-3-((5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl)thiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 3.04 mmol, 1.0 eq) was added to dichloromethane (10.0 mL), and trifluoroacetic acid (5.0 mL) was added dropwise. The mixture was reacted at room temperature for 1 h. The reaction was complete as monitored by TLC. The system was adjusted to pH 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10:1~6:1) to obtain the product (550.0 mg, yield: 55.0%)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 7.24-7.22 (d, J =8 Hz, 1H), 7.01-7.00 (m, 2H), 6.59-6.58 (d, J =4 Hz, 1H), 6.30 (s, 1H), 4.17 (s, 1H), 4.00-3.98 (m, 1H), 3.25-3.21 (m, 1H), 2.95-2.92 (m, 1H), 2.66-2.61 (m, 1H), 2.48 (s, 1H), 1.96-1.93 (m, 1H), 1.76-1.73 (m, 1H), 1.58-1.52 (m, 3H), 0.89-0.83 (m, 2H), 0.63-0.59 (m, 2H).

Molecular formula: C ₂₀ H ₂₂ N ₄ O Exact molecular weight: 334.18 LC-MS ( m/z ) = 335.20 [M + H] ⁺ .

Example 48: Synthesis of ( R )-2-(4- cyclopropyl -6-((1-(2- methoxyethyl ) piperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 240)

Step 1: Synthesis of (R )-6-chloro-5-cyclopropyl- N- (1-(2-methoxyethyl)piperidin-3-yl)pyridin-3-amine

( R )-6-chloro-5-cyclopropyl- N- (piperidin-3-yl)pyrimidine-3-amine (400.0 mg, 1.58 mmol, 1.0 eq), 1-bromo-2-methoxyethane (1.1 g, 7.90 mmol, 5.0 eq) and triethylamine (1.6 g, 15.8 mmol, 10.0 eq) were added to dichloromethane (15.0 mL) and stirred at room temperature for 14 h. The reaction was complete after TLC monitoring. Dichloromethane (100.0 mL) was added and the mixture was quenched with saturated aqueous ammonium chloride solution (50.0 The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1~30:1) to obtain the product (300.0 mg, yield: 61.0%).

Step 2: Synthesis of (R )-4-(4-cyclopropyl-6-((1-(2-methoxyethyl)piperidin-3-yl)amino)piperidin-3-yl)-3-(ethoxymethoxy)benzaldehyde

( R )-6-chloro-5-cyclopropyl- N- (1-(2-methoxyethyl)piperidin-3-yl)pyrimidine-3-amine (300.0 mg, 0.96 mmol, 1.0 eq.), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (354.5 mg, 1.15 mmol, 1.2 eq.), anhydrous potassium carbonate (200.0 mg, 1.44 mmol, 1.5 eq.) and Pd( _PPh3 ) ₄ (111.5 mg, 0.096 mmol, 0.1 eq.) were added to 1,4-dioxane (10.0 mL) and water (5.0 The mixture was added with 4% paraformaldehyde (2-hydroxy-1-nitropropene) and 4-nitropropene (2-hydroxy-1-nitropropene) (4-hydroxy-1-nitropropene) (6-hydroxy-1-nitropropene) (6-hydroxy-1-nitropropene) (7-hydroxy-1-nitropropene) (8-hydroxy-1-nitropropene) (9-hydroxy-1-nitropropene) (10-hydroxy-1-nitropropene) (2-hydroxy-1-nitropropene) (6-hydroxy-1-nitropropene) (8-hydroxy-1-nitropropene) (9-hydroxy-1-nitropropene) (10-hydroxy-1-nitropropene) (8-hydroxy-1-nitropropene) (6-hydroxy-1-nitropropene) (8-hydroxy-1-nitropropene) (9-hydroxy-1-nitropropene) (3-hydroxy-1-nitropropene) (3-hydroxy-1-nitropropene) (6-hydroxy-1-nitropropene) (3-hydroxy-1-nitropropene) (7-hydroxy-1-nitropropene) (8-hydroxy-1-nitropropene) (9-hydroxy-1-nitropropene) (3 ...

Step 3: Synthesis of (R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-(2-methoxyethyl)piperidin-3-yl)pyridin-3-amine

( R )-4-(4-cyclopropyl-6-((1-(2-methoxyethyl)piperidin-3-yl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde (280.0 mg, 0.61 mmol, 1.0 eq), dimethyl (1-diazo-2-oxopropyl)phosphonate (177.5 mg, 0.92 mmol, 1.5 eq) and anhydrous potassium carbonate (170.2 mg, 1.23 mmol, 2.0 eq) were added to methanol (10.0 mL) and reacted at room temperature for 14 h. The reaction was complete as monitored by LC-MS. The system was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=80:1~30:1) to obtain the product (170.0 mg, yield: 61.2%).

Step 4: Synthesis of (R )-2-(4-cyclopropyl-6-((1-(2-methoxyethyl)piperidin-3-yl)amino)thiazin-3-yl)-5-ethynylphenol

( R )-5-cyclopropyl-6-(2-(ethoxymethoxy)-4-ethynylphenyl) -N- (1-(2-methoxyethyl)piperidin-3-yl)pyrimidine-3-amine (140.0 mg, 0.31 mmol, 1.0 eq.) was added to dichloromethane (3.0 mL), and trifluoroacetic acid (1.0 mL) was added dropwise. The reaction was carried out at room temperature for 1 h. The reaction was completed as monitored by TLC. The system was adjusted to pH = 8-9 with saturated sodium carbonate aqueous solution, extracted with dichloromethane (100.0 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (40.0 mg, yield: 32.7%)

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.01 (s, 1H), 7.24-7.22 (d, J =8 Hz, 1H), 7.01-6.99 (m, 2H), 6.46 (s, 1H), 6.30 (s, 1H), 4.18 (s, 1H), 4.01 (s, 1H), 3.44 (s, 2H), 3.23 (s, 3H), 2.97 (s, 1H), 2.63 (s, 1H), 2.11-1.95 (m, 2H), 1.85-1.68 (m, 2H), 1.59-1.52 (m, 2H), 1.40-1.25 (m, 2H), 0.89-0.84 (m, 2H), 0.63-0.59 (m, 2H).

Molecular formula: C ₂₃ H ₂₈ N ₄ O ₂ Exact molecular weight: 392.22 LC-MS ( m / z ) = 393.22 [M + H] ⁺ .

Example 49: Synthesis of 2-(6-((( cis ) -3- hydroxy -3 -methylcyclobutyl ) amino )-4- methylpyridin - 3- yl )-5-(3,3,3- trifluoroprop -1- yn -1- yl ) phenol ( Compound 101)

Step 1: Synthesis of 4-bromo-3-hydroxybenzaldehyde

4-Bromo-3-methoxybenzaldehyde (10.00 g, 46.50 mmol, 1.0 eq) was added to HBr aqueous solution (48%, 100 mL), and the mixture was sealed and reacted at 100°C for 20 h in three batches. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature, and ethyl acetate (100 mL) and water (20 mL) were added. The aqueous phase was extracted with ethyl acetate (50 mL×2), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1~5:1) to obtain the product (6.10 g, yield: 65.3%).

Step 2: Synthesis of 4-bromo-3-(ethoxymethoxy)benzaldehyde

Dissolve 4-bromo-3-hydroxybenzaldehyde (6.10 g, 30.35 mmol, 1.0 eq) in THF (60 mL). Cool to 0°C and add NaH (60%, 2.43 g, 60.70 mmol, 2.0 eq) in portions. Stir for 30 min and then add chloromethoxyethane (4.30 mg, 45.52 mmol, 1.5 eq) dropwise. React at room temperature for 2 h. The reaction was complete as monitored by TLC, and a saturated NH ₄ Cl aqueous solution (10 mL) was added to quench the mixture. The mixture was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 100:1~10:1) to obtain the product (7.61 g, yield: 96.8%).

Step 3: Synthesis of 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde

4-Bromo-3-(ethoxymethoxy)benzaldehyde (3.80 g, 14.67 mmol, 1.0 eq), pinacol diborate (5.59 g, 22.00 mmol, 1.5 eq), Pd(dppf)Cl ₂ (0.54 g, 0.73 mmol, 0.05 eq) and potassium acetate (2.88 g, 29.33 mmol, 2.0 eq) were added to 1,4-dioxane (60 mL) and heated to 100°C for 12 h under nitrogen protection. The reaction was complete as monitored by TLC. The temperature was cooled to room temperature, filtered through diatomaceous earth, ethyl acetate (40 mL) was added, washed with saturated aqueous NaCl solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1~5:1) to obtain the product (3.53 g, yield: 78.6%).

Step 4: Synthesis of (cis )-3-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclobutan-1-ol

3,6-Dichloro-4-methylpyridinium chloride (3.00 g, 18.40 mmol, 1.0 eq) was dissolved in n-butanol (30 mL), ( cis )-3-amino-1-methylcyclobutan-1-ol hydrochloride (5.06 g, 36.81 mmol, 2.0 eq) and DIPEA (9.51 g, 73.62 mmol, 4.0 eq) were added, and the mixture was reacted at 120°C for 2 h. The reaction was complete as monitored by TLC, and the product was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1~2:1) to obtain the product (0.99 g, yield: 23.6%).

Step 5: Synthesis of 3-(ethoxymethoxy)-4-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridin-3-yl)benzaldehyde

3-(Ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.58 g, 5.16 mmol, 1.2 eq), ( cis )-3-((6-chloro-5-methylpyridin-3-yl)amino)-1-methylcyclobutan-1-ol (0.98 g, 4.30 mmol, 1.0 eq), Pd(dppf)Cl ₂ (0.31 g, 0.43 mmol, 0.1 eq) and sodium bicarbonate (0.72 g, 8.60 mmol, 2.0 eq) were added to a mixed solvent of 1,4-dioxane (22 mL) and water (5.5 mL) and heated to 110°C for 2 h under nitrogen protection. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature, water (25 mL) was added, and the mixture was extracted with ethyl acetate (25 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~10:1) to obtain the product (1.13 g, yield: 70.7%).

Step 6: Synthesis of (cis )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutan-1-ol

3-(Ethoxymethoxy)-4-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylphthalimide-3-yl)benzaldehyde (1.13 g, 3.04 mmol, 1.0 eq) and K ₂ CO ₃ (0.84 g, 6.08 mmol, 2.0 eq) were added to methanol (15 mL), and dimethyl (1-diazo-2-oxypropyl)phosphonate (0.88 g, 4.56 mmol, 1.5 eq) was added under stirring, and the reaction was carried out at room temperature for 2 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated, ethyl acetate (25 mL) was added, washed with water (15 mL×2), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~10:1) to obtain the product (1.07 g, yield: 95.7%).

Step 7: Synthesis of (cis )-3-((6-(2-(ethoxymethoxy)-4-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutan-1-ol

Togni reagent (377.3 mg, 1.14 mmol, 2.0 eq), CuI (65.3 mg, 0.34 mmol, 0.6 eq), 1,1-phenanthroline (61.8 mg, 0.34 mmol, 0.6 eq) and KHCO ₃ (114.4 mg, 1.14 mmol, 2.0 eq) were added to dichloromethane (5 mL). Under nitrogen protection, ( cis )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylphthalimino)-1-methylcyclobutan-1-ol (210.0 mg, 0.57 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL) and heated to 6 ℃. h and then slowly and evenly injected into the above reaction system. After the injection, stir at room temperature overnight. TLC showed that the reaction was complete. Water (10 mL) was added, and the liquid was separated. The aqueous phase was extracted with dichloromethane (5 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification was performed by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (131.5 mg, yield: 52.8%).

Step 8: Synthesis of 2-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-methylpyridin-3-yl)-5-(3,3,3-trifluoroprop-1-yn-1-yl)phenol

Dissolve ( cis )-3-((6-(2-(ethoxymethoxy)-4-(3,3,3-trifluoroprop-1-yn-1-yl)phenyl)-5-methylpyridin-3-yl)amino)-1-methylcyclobutan-1-ol (131.5 mg, 0.30 mmol) in dichloromethane (1 mL), add 4 mol/L hydrogen chloride solution in 1,4-dioxane (1 mL) dropwise, and react at room temperature for 5 min. The reaction was complete as monitored by TLC, and water (1 mL) was added to quench the reaction. The pH was adjusted to 8 with saturated NaHCO ₃ aqueous solution, and the mixture was extracted with dichloromethane (2 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (68.7 mg, yield: 60.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.45 (s, 1H), 7.31 (d, J = 8 Hz, 1H), 7.25-7.23 (m, 1H), 7.17 (d, J = 0.8 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 6.64 (s, 1H), 5.01 (s, 1H), 3.94-3.88 (m, 1H), 2.44-2.39 (m, 2H), 2.03 (s, 3H), 1.98-1.93 (m, 2H), 1.34-1.24 (m, 3H).

Molecular formula: C ₁₉ H ₁₈ F ₃ N ₃ O _2Exact molecular weight: 377.14 LC-MS ( m/z ) =378.30[M+H] ⁺ .

Example 50: Synthesis of ( R )-5- ethynyl -2-(4- methyl -6-( piperidin -3 -ylamino ) thiazol - 3- yl ) phenol ( Compound 139)

Step 1: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-methylphenyl)-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-chloro-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.20 g, 6.73 mmol, 1.0 eq), 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (2.47 g, 8.08 mmol, 1.2 eq), Pd(dppf) _Cl2 (0.49 g, 0.67 mmol, 0.1 eq) and sodium bicarbonate (1.13 g, 13.46 mmol, 2.0 eq) were added to a mixed solvent of 1,4-dioxane (40 mL) and water (10 mL). The mixture was heated to 110°C for 2 h under nitrogen protection. The reaction was complete as monitored by TLC. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~10:1) to obtain the product (2.68 g, yield: 84.6%).

Step 2: Synthesis of (R )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-(2-(ethoxymethoxy)-4-formylphenyl)-5-methylphthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.68 g, 5.70 mmol, 1.0 eq) and _K2CO3 ( _1.57 g, 11.39 mmol, 2.0 eq) were added to methanol (30 mL), stirred and dimethyl (1-diazo-2-oxypropyl)phosphonate (1.64 g, 8.54 mmol, 1.5 eq) was added, and the reaction was carried out at room temperature for 2 h. The reaction was complete as monitored by TLC. The reaction solution was concentrated, ethyl acetate (50 mL) was added, washed with water (25 mL×2), separated, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~10:1) to obtain the product (2.32 g, yield: 87.3%).

Step 3: Synthesis of (R )-5-ethynyl-2-(4-methyl-6-(piperidin-3-ylamino)thiazol-3-yl)phenol

Dissolve ( R )-3-((6-(2-(ethoxymethoxy)-4-ethynylphenyl)-5-methylpiperidine-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (400.0 mg, 0.86 mmol, 1.0 eq) in dichloromethane (4 mL), add dropwise a 4 mol/L hydrogen chloride solution in 1,4-dioxane (2.0 mL, 8.14 mmol, 9.5 eq), and react at room temperature for 2 h. The reaction was complete as monitored by TLC, and water (2 mL) was added to quench the reaction. The pH was adjusted to 8 with saturated NaHCO ₃ aqueous solution, and the mixture was extracted with dichloromethane (5 mL×5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (169.8 mg, yield: 64.2%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.15 (s, 1H), 7.18-7.16 (m, 1H), 7.05-6.99 (m, 3H), 6.72 (s, 1H), 4.26-4.24 (m, 1H), 4.19 (s, 1H), 3.45-3.41 (m, 1H), 3.17-3.14 (m, 2H), 2.88 (t, J = 10 Hz, 1H), 2.78 (t, J = 10.6 Hz, 1H), 2.04 (s, 4H), 1.91-1.90 (m, 1H), 1.75-1.73 (m, 1H), 1.72-1.60 (m, 1H).

Molecular formula: C ₁₈ H ₂₀ N ₄ O Exact molecular weight: 308.16 LC-MS ( m/z ) =309.28[M+H] ⁺ .

Example 51: ( R )-2-(4 -difluoromethyl -6-((1- methylpiperidin -3- yl ) amino ) thiazol - 3- yl )-5- ethynylphenol ( Compound 115)

Step 1: Synthesis of (R )-3-((6-chloro-5-difluoromethylphthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-4-difluoromethylthiazolidine (1.92 g, 9.65 mmol, 1.0 eq) was dissolved in N , N -dimethylacetamide (20 mL), and ( R )-1-tert-butoxycarbonyl-3-aminopiperidine (3.87 g, 19.3 mmol, 2.0 eq) and N , N -diisopropylethylamine (2.49 g, 19.3 mmol, 2.0 eq) were added thereto. The mixture was reacted at 120℃ for 1.5 h. The reaction was almost complete as determined by TLC. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1~15:1) to obtain the product (1.38 g, yield: 39.4%).

Step 2: Synthesis of the intermediate ( R )-6-chloro-5-difluoromethyl- N- (piperidin-3-yl)pyrimidine-3-amine

Dissolve ( R )-3-((6-chloro-5-difluoromethylthiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.38 g, 3.8 mmol, 1.0 eq) in dichloromethane (10 mL), drop into trifluoroacetic acid (10 mL), react at 25°C for 5 min, and the reaction is complete by TLC. Concentrate the reaction solution, adjust the concentrated solution to weak alkalinity with saturated sodium bicarbonate aqueous solution, extract the aqueous phase with dichloromethane:methanol=5:1 (10 mL×15), combine the organic phases, dry over anhydrous magnesium sulfate, and concentrate to obtain the crude product, which is directly used in the next step.

Step 3: Synthesis of the intermediate ( R )-6-chloro-5-difluoromethyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-6-Chloro-5-difluoromethyl- N- (piperidin-3-yl)pyrimidine-3-amine (crude product, 3.8 mmol, 1.0 eq) was dissolved in methanol (10 mL). A 37% formaldehyde aqueous solution (308 mg, 3.8 mmol, 1.0 eq) was added thereto. The mixture was reacted at 25°C for 2 h. Sodium cyanoborohydride (263 mg, 4.18 mmol, 1.1 eq) was added thereto. The mixture was reacted at 25°C for 5 min. The reaction was completed by TLC. The reaction solution was concentrated, and a saturated sodium bicarbonate aqueous solution (20 mL) was added to the concentrated solution. The mixture was extracted with dichloromethane (20 mL×5). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~10:1) to obtain the product (641 mg, two-step yield: 61.0%).

Step 4: Synthesis of the intermediate ( R )-4-(4-difluoromethyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)-3-ethoxymethoxybenzaldehyde

( R )-6-Chloro-5-difluoromethyl- N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (641 mg, 2.32 mmol, 1.0 eq) was dissolved in 1,4-dioxane (8 mL). 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (1.42 g, 4.64 mmol, 2.0 eq), an aqueous solution (2 mL) of potassium carbonate (641 mg, 4.64 mmol, 2.0 eq) and tetrakis(triphenylphosphine)palladium (268 mg, 0.232 mmol, 0.1 eq) were added thereto. The temperature was raised to 90°C under nitrogen protection for 2 h. The reaction was complete as determined by TLC. Dichloromethane (10 mL) was added to the reaction solution, dried over anhydrous magnesium sulfate, filtered through diatomaceous earth, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~20:1) to obtain the product (707 mg, yield: 72.5%).

Step 5: Synthesis of the intermediate ( R )-5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl) -N- (1-methylpiperidin-3-yl)pyrimidine-3-amine

( R )-4-(4-difluoromethyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)-3-ethoxymethoxybenzaldehyde (707 mg, 1.68 mmol, 1.0 eq) was dissolved in methanol (10 mL), potassium carbonate (465 mg, 3.36 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (484 mg, 2.52 mmol, 1.5 eq) were added thereto, and the mixture was reacted at 25°C for 1 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, water (20 mL) was added thereto, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~20:1) to obtain the product (403 mg, yield: 57.6%).

Step 6: Synthesis of compound ( R )-2-(4-difluoromethyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)-5-ethynylphenol

( R )-5-difluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl) -N- (1-methylpiperidin-3-yl)pyrimidine-3-amine (403 mg, 0.968 mmol) was dissolved in dichloromethane (4 mL) and slowly added dropwise to trifluoroacetic acid (4 mL). The mixture was reacted at 25°C for 5 min. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by silica gel column chromatography (dichloromethane:methanol = 100:1~10:1) to obtain the product (150 mg, yield: 43.2%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.26 (s, 1H), 7.27-7.25 (d, 1H), 7.21-7.19 (d, 1H), 7.11 (s, 1H), 7.04-7.03 (m, 2H), 6.90-6.03 (t, 1H), 4.22 (s, 1H), 4.18 (m, 1H), 2.97 (m, 1H), 2.68-2.65 (m, 1H), 2.30 (s, 3H), 2.15-2.12 (m, 2H), 1.87-1.76 (m, 2H), 1.62-1.34 (m, 2H).

Molecular formula: C ₁₉ H ₂₀ F ₂ N ₄ O Exact molecular weight: 358.16 LC-MS(m/z): 359.18[M+H] ⁺ .

Example 52: 5- ethynyl -2-(6-((( cis )-3 - hydroxy -3- methylcyclobutyl ) amino )-4 - trifluoromethylbenzyl -3- yl ) phenol ( Compound 239)

Step 1: Synthesis of the intermediate ( cis )-3-((6-chloro-5-trifluoromethylindole-3-yl)amino)-1-methylcyclobutyl-1-ol

3,6-Dichloro-4-trifluoromethyl pyroxene (1.5 g, 6.91 mmol, 1.0 eq) was dissolved in n-butanol (15 mL), and ( cis )-3-amino-1-methylcyclobutyl-1-ol hydrochloride (1.9 g, 13.82 mmol, 2.0 eq) and N , N -diisopropylethylamine (3.6 g, 27.64 mmol, 4.0 eq) were added thereto. The mixture was reacted at 120°C for 0.5 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 10:1~1:1) to obtain the product (1.16 g, yield: 59.5%).

Step 2: Synthesis of the intermediate 4-(4-trifluoromethyl-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)benzaldehyde

Dissolve ( cis )-3-((6-chloro-5-trifluoromethylbenzyl)amino)-1-methylcyclobutyl-1-ol (600 mg, 2.13 mmol, 1.0 eq) in 1,4-dioxane (6 mL), add 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzaldehyde (1.3 g, 4.26 mmol, 2.0 eq), potassium carbonate (589 mg, 4.26 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (246 mg, 0.213 mmol, 0.1 eq) and water (1.5 mL), and heat to 90°C under nitrogen for 2 h. The reaction is complete as determined by TLC. The reaction solution was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane (10 mL). The filtrate was combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~3:1) to obtain the product (700 mg, yield: 77.3%).

Step 3: Synthesis of the intermediate ( cis )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)pyrimidine-3-yl)amino)-1-methylcyclobutyl-1-ol

4-(4-Trifluoromethyl-6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)thiazol-3-yl)-3-(ethoxymethoxy)benzaldehyde (700 mg, 1.645 mmol, 1.0 eq) was dissolved in methanol (10 mL), potassium carbonate (455 mg, 3.290 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (474 mg, 2.468 mmol, 1.5 eq) were added thereto, and the mixture was reacted at 25°C for 1 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~50:1) to obtain the product (100 mg, yield: 14.4%).

Step 4: Synthesis of compound 5-ethynyl-2-(6-((( cis )-3-hydroxy-3-methylcyclobutyl)amino)-4-trifluoromethylphthalimide-3-yl)phenol

( cis )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)oxathiazol-3-yl)amino)-1-methylcyclobutyl-1-ol (100 mg, 0.237 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL) and added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 5 min. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain the product (38 mg, yield: 44.2%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.83 (s, 1H), 7.64-7.62 (d, 1H), 7.14 (s, 1H), 7.13 (s, 1H), 6.99-6.97 (m, 2H), 5.06 (s, 1H), 4.20 (s, 1H), 4.06-3.98 (m, 1H), 2.48-2.43 (m, 2H), 2.01-1.96 (m, 2H), 1.30 (s, 3H).

Molecular formula: C ₁₈ H ₁₆ F ₃ N ₃ O ₂ Exact molecular weight: 363.12 LC-MS ( m/z ): 364.15 [M+H] ⁺ .

Example 53: ( R )-5- ethynyl -2-(6-( piperidin -3 -ylamino )-4- trifluoromethylpiperidin -3- yl ) phenol ( Compound 161 )

Step 1: Synthesis of compound ( R )-3-((6-chloro-5-trifluoromethylthiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

3,6-Dichloro-4-trifluoromethylthiazolidine (3.0 g, 13.83 mmol, 1.0 eq) was dissolved in DMAc (30 mL), and ( R )-1-tert-butoxycarbonyl-3-aminopiperidine (5.5 g, 27.66 mmol, 2.0 eq) and N , N -diisopropylethylamine (3.6 g, 27.66 mmol, 2.0 eq) were added thereto. The mixture was reacted at 120°C for 0.5 h. The reaction was complete as detected by TLC. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (40 mL×4), the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 40:1~10:1) to obtain the product (3.53 g, yield: 67.0%).

Step 2: Synthesis of the intermediate ( R )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-formaldehydephenyl)phthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((6-chloro-5-trifluoromethylpyridin-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 5.25 mmol, 1.0 eq) was dissolved in 1,4-dioxane (20 mL). 3-(ethoxymethoxy)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (3.21 g, 10.5 mmol, 2.0 eq), potassium carbonate (1.45 g, 10.5 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium (607 mg, 0.525 mmol, 0.1 eq) and water (5 mL) were added thereto. The temperature was raised to 90°C under nitrogen protection for 2 h. The reaction was completed by TLC detection. The reaction solution was filtered through diatomaceous earth, water (20 mL) was added to the filtrate, and the mixture was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1~1:1) to obtain the product (2.25 g, yield: 81.8%).

Step 3: Synthesis of the intermediate ( R )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)phthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-formaldehydephenyl)phthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.25 g, 4.29 mmol, 1.0 eq) was dissolved in methanol (25 mL), potassium carbonate (1.19 g, 8.58 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (1.24 g, 6.44 mmol, 1.5 eq) were added thereto, and the mixture was reacted at 25°C for 1 h. The reaction was complete as determined by TLC. The reaction solution was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 8:1~2:1) to obtain the product (400 mg, yield: 17.9%).

Step 4: Synthesis of compound ( R )-5-ethynyl-2-(6-(piperidin-3-ylamino)-4-trifluoromethylthiazol-3-yl)phenol

( R )-3-((5-trifluoromethyl-6-(2-ethoxymethoxy-4-ethynylphenyl)thiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 0.768 mmol, 1.0 eq) was dissolved in dichloromethane (4 mL), added dropwise to trifluoroacetic acid (4 mL), and reacted at 25°C for 5 min. The reaction was complete by TLC detection. The reaction solution was concentrated, dichloromethane (10 mL) and water (10 mL) were added to the concentrated solution, and the liquids were separated. The pH value of the aqueous phase was adjusted to weak alkalinity with sodium bicarbonate, and extracted with dichloromethane:methanol=5:1 (10 mL×20). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to obtain a crude product. Half of the crude product was taken and purified by preparative thin layer chromatography (dichloromethane:methanol=7:1) to obtain the product (70 mg, yield: 50.4%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 7.37-7.35 (d, 1H), 7.22 (s, 1H), 7.14-7.12 (m, 1H), 6.99-6.97 (m, 2H), 4.17 (s, 1H), 4.07 (s, 1H), 3.24-3.21 (m, 1H), 2.93-2.90 (m, 1H), 2.66-2.53 (m, 2H), 2.00-1.98 (m, 1H), 1.77-1.74 (m, 1H), 1.57-1.50 (m, 2H).

Molecular formula: C ₁₈ H ₁₇ F ₃ N ₄ O Exact molecular weight: 362.14 LC-MS ( m / z ): 363.15 [M+H] ⁺ .

Example 54: ( R )-5- ethynyl -2-(4- trifluoromethyl -6-((1- methylpiperidin -3- yl ) amino ) piperidin - 3- yl ) phenol ( Compound 114)

Step 1: Synthesis of (R )-5-ethynyl-2-(4-trifluoromethyl-6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)phenol

( R )-5-ethynyl-2-(6-(piperidin-3-yl)amino)-4-trifluoromethylphthalimide-3-yl)phenol (crude, 0.384 mmol, 1.0 eq) was dissolved in methanol (2 mL). A 37% formaldehyde aqueous solution (32 mg, 0.384 mmol, 1.0 eq) and sodium cyanoborohydride (27 mg, 0.422 mmol, 1.1 eq) were added. The mixture was reacted at 25°C for 5 min. The reaction was completed by TLC. The reaction solution was concentrated, saturated brine (5 mL) was added to the reaction solution, and extracted with a mixed solvent of dichloromethane: methanol = 10:1 (10 mL×6), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative thin layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (60 mg, yield: 41.7%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.93 (s, 1H), 7.32-7.30 (d, 1H), 7.25 (s, 1H), 7.14-7.12 (d, 1H), 6.99-6.67 (s, 2H), 4.17 (s, 1H), 4.15-4.10 (m, 1H), 2.88-2.86 (m, 1H), 2.55 (m, 1H), 2.23 (s, 3H), 2.17 (m, 1H), 2.09 (m, 1H), 1.83 (m, 1H) , 1.76-1.73 (m, 1H), 1.61-1.53 (m, 1H), 1.39-1.37 (m, 1H).

Molecular formula: C ₁₉ H ₁₉ F ₃ N ₄ O Exact molecular weight: 376.15 LC-MS ( m / z ): 377.17 [M+H] ⁺ .

Example 55: ( R )-5- ethynyl -2-(6-((1-(2- hydroxyethylpiperidinyl )-3- yl ) amino )-4- trifluoromethylpiperidin -3- yl ) phenol ( Compound 163 )

Step 1: Synthesis of (R )-6-chloro- N- (piperidin-3-yl)-5-trifluoromethylpiperidin-3-amine

Dissolve ( R )-3-((6-chloro-5-trifluoromethylphthalimino)piperidine-1-carboxylic acid tert-butyl ester (860 mg, 2.26 mmol, 1.0 eq) in dichloromethane (8 mL), drop into trifluoroacetic acid (8 mL), react at 25°C for 5 min, and the reaction is complete by TLC. Concentrate the reaction solution, adjust the concentrated solution to weak alkalinity with saturated sodium bicarbonate aqueous solution, extract the aqueous phase with dichloromethane:methanol=5:1 (10 mL×15), combine the organic phases, dry over anhydrous magnesium sulfate, and concentrate to obtain a crude product, which is directly used in the next step.

Step 2: Synthesis of the intermediate ( R )-2-(3-((6-chloro-5-trifluoromethylpiperidin-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-6-Chloro- N- (piperidin-3-yl)-5-trifluoromethylpyridin-3-amine (crude product, 2.26 mmol, 1.0 eq) was dissolved in dichloromethane (10 mL). Triethylamine (2.29 g, 22.6 mmol, 10.0 eq) and bromoethanol (1.41 g, 11.3 mmol, 5.0 eq) were added thereto. The mixture was reacted at 25°C for 24 h. The reaction was completed by TLC detection. The reaction solution was poured into a saturated aqueous ammonium chloride solution (10 mL), extracted with dichloromethane (10 mL×4), the organic phases were combined, dried over anhydrous magnesium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol = 100:1~10:1) to obtain the product (730 mg, two-step yield: 99.5%).

Step 3: Synthesis of the intermediate ( R )-3-ethoxymethoxy-4-(6-((1-(2-hydroxyethyl)piperidinyl)-3-yl)amino-4-trifluoromethylpiperidin-3-yl)benzaldehyde

( R )-2-(3-((6-chloro-5-trifluoromethylpyridin-3-yl)amino)piperidin-1-yl)ethan-1-ol (500 mg, 1.54 mmol, 1.0 eq) was dissolved in 1,4-dioxane (5 mL), 3-ethoxymethoxy-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (566 mg, 1.85 mmol, 1.2 eq) and an aqueous solution (1 mL) of potassium carbonate (426 mg, 3.08 mmol, 2.0 eq) and tetrakis(triphenylphosphine)palladium (178 mg, 0.154 mmol, 0.1 eq) were added thereto, and the temperature was raised to 90°C under nitrogen protection for 5 minutes. h, TLC detected that the reaction was complete. The reaction solution was filtered through diatomaceous earth, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane:methanol=100:1~50:1) to obtain the product (280 mg, yield: 38.8%).

Step 4: Synthesis of the intermediate ( R )-2-(3-((6-2-ethoxymethoxy-4-ethynylphenyl)-5-trifluoromethylpiperidin-3-yl)amino)piperidin-1-yl)ethan-1-ol

( R )-3-Ethoxymethoxy-4-(6-((1-(2-hydroxyethyl)piperidinyl)-3-yl)amino-4-trifluoromethylphthalimide-3-yl)benzaldehyde (140 mg, 0.3 mmol, 1.0 eq) was dissolved in methanol (10 mL), potassium carbonate (83 mg, 0.6 mmol, 2.0 eq) and dimethyl (1-diazo-2-oxopropyl)phosphonate (87 mg, 0.45 mmol, 1.5 eq) were added thereto, and the mixture was reacted at 25°C for 1.5 h. The reaction was complete as detected by TLC. The reaction solution was concentrated, water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL×3). The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 10:1) to obtain the product (43 mg, yield: 30.9%).

Step 5: Synthesis of compound ( R )-5-ethynyl-2-(6-((1-(2-hydroxyethyl)piperidin-3-yl)amino)-4-trifluoromethylpiperidin-3-yl)phenol

( R )-2-(3-((6-2-ethoxymethoxy-4-ethynylphenyl)-5-trifluoromethylpyridin-3-yl)amino)piperidin-1-yl)ethan-1-ol (43 mg, 0.918 mmol) was dissolved in dichloromethane (1 mL) and slowly added dropwise to trifluoroacetic acid (1 mL). The mixture was reacted at 25°C for 1 hour. The reaction was complete as determined by TLC. The reaction solution was concentrated and the crude product was purified by preparative thin layer chromatography (dichloromethane:methanol=10:1) to obtain the product (20 mg, yield: 54.1%).

¹ H-NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 9.86 (s, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.15-7.13 (m, 1H), 6.98-6.97 (m, 2H), 4.40 (s, 1H), 4.21 (s, 2H), 3.55 (m, 2H), 3.12-2.93 (m, 1H), 2.81-2.67 (m, 1H), 2.61-2.53 (m, 2H), 2.48-2.17 (m, 2H), 1.92-1.76 (m, 2H), 1.59-1.46 (m, 2H).

Molecular formula: C ₂₀ H ₂₁ F ₃ N ₄ O ₂ Exact molecular weight: 406.16 LC-MS (m/z): 407.17 [M + H] ⁺ .

Example 56: ( R )-3-(4- ethynyl -2- hydroxyphenyl )-4- isopropyl -6-((1- methylpiperidin -3 -yl ) amino )-1,2,4- trioxan - 5( 4H )-one ( Compound 112 )

Step 1: Synthesis of 4-bromo- N -isopropyl-2-methoxybenzamide

Under ice bath, add isopropylamine (23 g, 389.52 mmol, 3.0 eq) dropwise to a solution of 4-bromo-2-methoxybenzyl chloride (32.39 g, 129.84 mmol, 1.0 eq) in dichloromethane (300 mL) and react for 10 min. TLC indicates that the reaction is complete, pour the reaction solution into water (200 mL), extract with dichloromethane (200 mL×2), combine the organic phases, dry, and concentrate to obtain the product (35.33 g, yield: 100%).

Step 2: Synthesis of 4-bromo- N -isopropyl-2-methoxythiobenzamide

4-Bromo- N -isopropyl-2-methoxybenzamide (35.33 g, 129.84 mmol, 1.0 eq) and Lawson reagent (28.88 g, 71.41 mmol, 0.55 eq) were dissolved in THF (300 mL) and reacted at 60°C for 2 h. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:15) to obtain the product (30 g, yield: 80.1%).

Step 3: Synthesis of methyl 4-bromo- N -isopropyl-2-methoxythiobenzoylimidate

4-Bromo- N -isopropyl-2-methoxythiobenzamide (30 g, 104.09 mmol, 1.0 eq) and iodomethane (29.55 g, 208.18 mmol, 2.0 eq) were dissolved in THF (300 mL) and reacted at room temperature for 17 h. TLC detected that the reaction was complete, and the reaction solution was poured into water (300 mL), and the pH value was adjusted to about 9 with potassium carbonate, and extracted with ethyl acetate (200 mL×2), and the organic phases were combined, dried, and concentrated to obtain the product (31.45 g, yield: 100%).

Step 4: Synthesis of N -amino-4-bromo-2-methoxy- N' -isopropyl-benzamidine

Dissolve 4-bromo- N -isopropyl-2-methoxythiobenzoylimidate (31.45 g, 108.09 mmol, 1.0 eq) and hydrazine hydrate (6.13 g, 104.09 mmol, 1.0 eq) in EtOH (300 mL) and react at 80°C for 5 h. The reaction was complete as monitored by LC-MS. The reaction solution was concentrated under reduced pressure, and the crude product was slurried with methyl tert-butyl ether (200 mL) and filtered to obtain the product (20 g, yield: 67.2%).

Step 5: Synthesis of 6-amino-3-(4-bromo-2-methoxyphenyl)-4-isopropyl-1,2,4-trioxan-5( 4H )-one

N -amino-4-bromo-2-methoxy- N' -isopropyl-benzamidine (20 g, 69.9 mmol, 1.0 eq), ethyl thioxamate (9.31 g, 69.9 mmol, 1.0 eq) and ethyl acetate (14.15 g, 139.8 mmol, 2.0 eq) were dissolved in EtOH (200 mL) and reacted at 70°C for 25 h. The reaction was complete as monitored by TLC, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:2) to obtain the product (6.5 g, yield: 27.4%).

Step 6: Synthesis of 6-bromo-3-(4-bromo-2-methoxyphenyl)-4-isopropyl-1,2,4-trioxan-5( 4H )-one

6-amino-3-(4-bromo-2-methoxyphenyl)-4-isopropyl-1,2,4-trioxan-5(4 H )-one (6.5 g, 19.16 mmol, 1.0 eq) and CuBr (5.50 g, 38.32 mmol, 2.0 eq) were dispersed in ACN (65 mL). Under nitrogen protection, tert-butyl nitrite (3.95 g, 38.32 mmol, 2.0 eq) was slowly added dropwise at 70°C for 0.5 h. The reaction was complete as monitored by LC-MS. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:5) to obtain the product (2.4 g, yield: 31.1%).

Step 7: Synthesis of (R )-3-((3-(4-bromo-2-methoxyphenyl)-4-isopropyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

6-Bromo-3-(4-bromo-2-methoxyphenyl)-4-isopropyl-1,2,4-trioxan-5( 4H )-one (2.4 g, 5.95 mmol, 1.0 eq), ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (1.43 g, 7.14 mmol, 1.2 eq) and DIPEA (1.54 g, 11.9 mmol, 2.0 eq) were dissolved in 1,4-dioxane (25 mL) and reacted at 100℃ for 20 h. The reaction was complete as monitored by TLC. The reaction solution was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried and concentrated to obtain the product (2.4 g, yield: 77.4%).

Step 8: Synthesis of (R )-3-((4-isopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

( R )-3-((3-(4-bromo-2-methoxyphenyl)-4-isopropyl-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.4 g, 4.59 mmol, 1.0 eq), trimethylsilylene (2.25 g, 22.95 mmol, 5.0 eq), _PdCl2 ( _PPh3 ) ₂ (323 mg, 0.46 mmol, 0.1 eq) and CuI (263 mg, 1.38 mmol, 0.3 eq) were dispersed in THF (20 mL) and diisopropylamine (20 mL) and reacted at 60°C for 24 h under nitrogen protection. The reaction was complete as determined by TLC. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 1:3) to obtain the product (2.0 g, yield: 88.7%).

Step 9: Synthesis of (R )-4-isopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-3-((4-isopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-5-oxo-4,5-dihydro-1,2,4-trioxan-6-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (2.2 g, 4.08 mmol, 1.0 eq) in ethyl acetate (20 mL), add a solution of hydrogen chloride in 1,4,-dioxane (4 mol/L, 10 mL), and react at room temperature for 2 h. TLC detection shows that the reaction is complete, and the reaction solution is poured into water (30 mL), and the pH value is adjusted to about 9 with sodium carbonate, and extracted with ethyl acetate (30 mL×2), and the organic phases are combined, dried, and concentrated to obtain the product (1.7 g, yield: 100%).

Step 10: Synthesis of (R )-4-isopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-trioxan-5( 4H )-one

( R )-4-isopropyl-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (0.5 g, 1.13 mmol, 1.0 eq) and aqueous formaldehyde solution (37%, 92 mg, 1.13 mmol, 1.0 eq) were dissolved in methanol (20 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (71 mg, 1.13 mmol, 1.0 eq) was added and the reaction was carried out at room temperature for 10 min. The reaction was complete as monitored by TLC. The reaction solution was concentrated under reduced pressure. The crude product was dispersed with water (10 mL) and extracted with dichloromethane (20 mL×2). The organic phases were combined, dried, and concentrated to obtain the product (513 mg, yield: 100%).

Step 11: Synthesis of (R )-3-(4-ethynyl-2-hydroxyphenyl)-4-isopropyl-6-((1-methylpiperidin-3-yl)amino)-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-4-isopropyl-6-((1-ethylpiperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-1,2,4-trioxan-5( 4H )-one (513 mg, 1.13 mmol, 1.0 eq) in dichloromethane (20 mL), cool to -60°C, add boron tribromide (1.42 g, 5.65 mmol, 5.0 eq), and naturally warm to room temperature for reaction for 17 h. The reaction was complete as detected by TLC. An appropriate amount of methanol was added to the reaction solution, and the solution was concentrated under reduced pressure. The crude product was dispersed with water (20 mL), and the pH value was adjusted to about 8 with sodium bicarbonate. The product was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated. The crude product was purified by preparative thin-layer chromatography (dichloromethane: methanol = 10:1) to obtain the product (80 mg, yield: 19.3%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.43 (s, 1H), 7.32-7.30 (d, 1H), 7.04-7.02 (d, 2H), 6.91 (s, 1H), 4.28 (s, 1H), 4.06-4.03 (t, 1H), 3.91-3.85 (m, 1H), 2.90 (s, 1H), 2.68 (s, 1H), 2.35 (s, 5H), 1.73 (s, 2H), 1.58 (s, 2H), 1.43-1.41 (d, 6H).

Molecular formula: C ₂₀ H ₂₅ N ₅ O ₂ Exact molecular weight: 367.20 LC-MS ( m/z ) = 368.24 [M+H] ⁺ .

Example 57: ( R )-3-(4- ethynyl -2- hydroxyphenyl )-4- methyl -6-( piperidin -3 -ylamino )-1,2,4- trioxan - 5 ( 4H )-one ( Compound 201 )

Step 1: Synthesis of ( R )-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one

Dissolve ( R )-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (0.3 g, 0.72 mmol, 1.0 eq) in dichloromethane (5 mL), cool to -70°C, add boron tribromide (541 mg, 2.16 mmol, 3.0 eq), and naturally warm to room temperature for reaction for 16 h. The reaction was complete as detected by LC-MS. An appropriate amount of methanol was added to the reaction solution, and the solution was concentrated under reduced pressure. The crude product was dissolved in methanol (20 mL), and the pH value was adjusted to about 9 with an aqueous sodium bicarbonate solution. The crude product was first chromatographed on a silica gel column (dichloromethane: methanol = 10: 1) to obtain a crude product (100 mg), and then purified by silica gel column chromatography (dichloromethane: methanol = 12: 1) to obtain the product (12 mg, yield: 5.1%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.46 (s, 1H), 8.63 (s, 1H), 7.38-7.36 (d, 1H), 7.32-7.30 (d, 1H) 7.06-7.04 (d, 2H), 4.30 (s, 1H), 4.26-4.25 (d, 1H), 3.39 (s, 1H), 3.32 (s, 1H), 3.19 (s, 3H), 2.96-2.90 (t, 1H), 2.87-2.85 (t, 1H), 1.95-1.90 (d, 2H), 1.74-1.71 (d, 2H).

Molecular formula: C ₁₇ H ₁₉ N ₅ O _2Molecular weight: 325.15 LC-MS ( m/z ) = 326.18 [M+H] ⁺ .

Example 58: ( R )-6-((1-(2,2 -difluoroethyl ) piperidin -3- yl ) amino )-3-(4- ethynyl -2- hydroxyphenyl )-4- methyl -1,2,4- triazine - 5 ( 4H )-one ( Compound 204 )

Step 1: Synthesis of (R )-6-((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one

( R )-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-6-(piperidin-3-ylamino)-1,2,4-trioxan-5( 4H )-one (0.5 g, 1.21 mmol, 1.0 eq), potassium carbonate (334 mg, 2.42 mmol, 2.0 eq) and 1,1-difluoro-2-iodoethane (464 mg, 2.42 mmol, 2.0 eq) were added to DMF (10 mL) and reacted at 80°C for 16 h. LC-MS detected that the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated. The crude product was purified by silica gel column chromatography (dichloromethane: methanol = 40: 1) to obtain the product (200 mg, yield: 41.0%).

Step 2: Synthesis of (R )-6-((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-3-(4-ethynyl-2-hydroxyphenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one

( R )-6-((1-(2,2-difluoroethyl)piperidin-3-yl)amino)-3-(2-methoxy-4-((trimethylsilyl)ethynyl)phenyl)-4-methyl-1,2,4-trioxan-5( 4H )-one (200 mg, 0.49 mmol, 1.0 eq) was dissolved in dichloromethane (5 mL), cooled to -60°C, and boron tribromide (614 mg, 2.45 mmol, 5.0 eq) was added. The temperature was naturally raised to room temperature for reaction for 4 h. The reaction was complete as detected by LC-MS. An appropriate amount of methanol was added to the reaction solution. The reaction solution was concentrated under reduced pressure. The crude product was dissolved in water (20 mL). The pH value was adjusted to about 8 with sodium bicarbonate. The product was extracted with ethyl acetate (20 mL×3). The organic phases were combined, dried, and concentrated. The crude product was purified by preparative thin layer chromatography (ethyl acetate: methanol = 10:1) to obtain the product (40 mg, yield: 21%).

¹ H NMR (400 MHz, DMSO- d ₆ ) δ(ppm): 10.42 (s, 1H), 7.32-7.30 (d, 1H), 7.05-703 (t, 2H), 6.88-6.86 (d, 1H), 6.29-6.01 (t, 1H), 4.28 (s, 1H), 4.05-4.01 (t, 1H), 3.18 (s, 3H), 2.94-2.92 (d, 1H), 2.80-2.69 (m, 3H), 2.33 (s, 2H), 1.72-1.66 (t, 2H), 1.58-1.51 (m, 2H).

Molecular formula: C ₁₉ H ₂₁ F ₂ N ₅ O _2Exact molecular weight: 389.17 LC-MS ( m/z ) = 390.18 [M+H] ⁺ .

Example 59: Synthesis of ( R )-3,5- dimethyl -2-(6-((1- methylpiperidin -3- yl ) amino ) piperidin - 3- yl ) phenol ( reference )

Step 1: Synthesis of 2-iodo-3,5-dimethylphenol

Dissolve 3,5-dimethylphenol (10.0 g, 81.9 mmol, 1.0 eq) in xylene (500 mL) and cool to 0°C under nitrogen. Add NaH (6.55 g, 164 mmol, 2.0 eq) in batches. After addition, react at 0°C for 30 min and then warm to room temperature for 1 h. Cool to 0°C and dropwise add a solution of iodine (20.7 g, 81.9 mmol, 1.0 eq) in xylene (250 mL). After addition, react for 30 min. After the reaction was complete, 0.5 mol/L dilute hydrochloric acid was added to quench the reaction, and EA was extracted (200 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=100:1) to obtain the product (5.2 g, yield: 25.6%).

Step 2: Synthesis of 2-iodo-1-methoxy-3,5-dimethylbenzene

2-iodo-3,5-dimethylphenol (2.0 g, 8.06 mmol, 1.0 eq) and potassium carbonate (2.23 g, 16.1 mmol, 2.0 eq) were added to DMF (20 mL), and iodomethane (1.72 g, 12.1 mmol, 1.5 eq) was added under stirring. The mixture was reacted at room temperature for 2 h. After the reaction was complete, water was added, and EA was extracted (50 mL×3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE:EA=100:1) to obtain the product (1.9 g, yield: 89.9%).

Step 3: Synthesis of (2-methoxy-4,6-dimethylphenyl)boronic acid

Dissolve 2-iodo-1-methoxy-3,5-dimethylbenzene (1.8 g, 6.87 mmol, 1.0 eq) and triisopropyl borate (2.57 g, 13.7 mmol, 2.0 eq) in tetrahydrofuran (20 mL). Cool to -78°C under nitrogen protection, slowly add n-butyl lithium (2.5 mol/L n-hexane solution, 5.48 mL, 13.7 mmol, 2.0 eq) solution, keep at -78°C for 30 min after the addition, then slowly raise to room temperature for 2 h. After the reaction is complete, add 2 mol/L dilute hydrochloric acid to quench the reaction, and continue to stir and react for 0.5 h. EA extraction (20 mL×3), the organic phase was dried, filtered, and concentrated. The obtained crude product was slurried with PE and filtered to obtain the product (850 mg, yield: 68.8%).

Step 4: Synthesis of (R )-3-((6-chloro-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

Dissolve 3,6-dichloropyridinium (10.0 g, 67.1 mmol, 1.0 eq) and ( R )-3-aminopiperidine-1-carboxylic acid tert-butyl ester (16.1 g, 80.5 mmol, 1.2 eq) in n-butanol (100 mL). Heat to 115°C for 20 h under nitrogen. After the reaction is complete, reduce the pressure and concentrate. The residue is slurried with EA and filtered to obtain the product (16.5 g, yield: 78.6%).

Step 5: Synthesis of (R )-3-((6-(2-methoxy-4,6-dimethylphenyl)phthalimide-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester

(2-Methoxy-4,6-dimethylphenyl)boronic acid (800 mg, 4.44 mmol, 1.0 eq), ( R )-3-((6-chloro-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (1.39 g, 4.44 mmol, 1.0 eq), Pd(dppf)Cl2 (325 mg, 0.444 mmol, 0.1 eq) and sodium bicarbonate (746 mg, 8.88 mmol, 2.0 eq) were added to 1,4-dioxane (10 mL) and water (5 mL), react at 110°C for 2 h under nitrogen protection. After the reaction is complete, cool to room temperature, add water, extract with EA (50 mL×2), dry the organic phase, filter, concentrate, and purify the crude product by silica gel column chromatography (DCM:MeOH=100:1~50:1) to obtain the product (540 mg, yield: 29.5%).

Step 6: Synthesis of (R )-3,5-dimethyl-2-(6-(piperidin-3-ylamino)piperidin-3-yl)phenol

( R )-3-((6-(2-methoxy-4,6-dimethylphenyl)thiazol-3-yl)amino)piperidine-1-carboxylic acid tert-butyl ester (540 mg, 1.31 mmol, 1.0 eq) was added to DCM (5 mL), cooled to -10°C (ice-salt bath), and slowly added boron tribromide (1.64 g, 6.55 mmol). After the addition was complete, the temperature was naturally raised to room temperature for reaction. After the reaction was complete, methanol was added to quench the reaction, concentrated, diluted with water, adjusted to pH 8, extracted with DCM (30 mL×3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product (290 mg, yield: 74.2%).

Step 7: Synthesis of (R )-3,5-dimethyl-2-(6-((1-methylpiperidin-3-yl)amino)thiazol-3-yl)phenol

( R )-3,5-Dimethyl-2-(6-(piperidin-3-ylamino)phthalimide-3-yl)phenol (280 mg, 0.938 mmol, 1.0 eq) was dissolved in methanol (5 mL). Formaldehyde aqueous solution (37%, 230 mg, 2.81 mmol, 3.0 eq) was added and stirred at room temperature for 30 min. Sodium cyanoborohydride (177 mg, 2.81 mmol, 3.0 eq) was added and the reaction was allowed to react at room temperature for 2 h. After the reaction was complete, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with a DCM/MeOH = 10:1 mixed solution (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by reverse phase preparative chromatography (acetonitrile/water = 30%) to obtain the product (202 mg, yield: 68.9%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ: 9.49 (s, 1H), 7.16 (d, J = 9.2 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.67 (d, J = 7.8 Hz, 1H), 6.59-6.51 (m, 2H), 4.15-3.95 (m, 1H), 2.95-2.76 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.03 (s, 3H), 1.98-1.78 (m, 2H), 1.77-1.64 (m, 1H), 1.63-1.45 (m, 1H), 1.38-1.18 (m, 2H).

Molecular formula: C ₁₈ H ₂₄ N ₄ O Exact molecular weight: 312.19 LC-MS ( m/z )=313.26 [M+H] ⁺ .

Experimental example 1 ：Cells containing the compounds of the present invention NLRP3 Inflammasome inhibitory activity test

Test substance: Compound of the present invention, prepared according to the method of the embodiment

THP-1 is an immortalized human macrophage cell line

Testing instrument: ELISA instrument (made of PE)

Test method:

1. THP-1 cells were cultured in 1640 complete medium (500 mL 1640 + 56 mL FBS + 560 μL 1000× P/S + 2 μL ethanol) and used within 3-20 generations.

2. Coated culture plate: Add 100 μL poly-lysine solution to a 96-well cell culture plate and incubate at 37°C for 30 min. Discard the solution and wash twice with PBS for later use.

3. THP-1 induced differentiation: THP-1 cells were resuspended in an appropriate amount of complete culture medium containing 10 ng/mL PMA to a cell suspension density of 5×10^ ⁵ cells/mL, added to a 96-well plate, 100 μL of cell suspension per well, and cultured overnight in a 37°C carbon dioxide cell culture incubator for 16 h.

4. THP-1 stimulation:

a. Add serum-free THP-1 medium containing LPS to a final concentration of 500 ng/mL and incubate in a carbon dioxide cell culture incubator at 37°C for 3 h;

b. Prepare the test compound with DMSO to prepare a gradient concentration of the stock solution, add it to the cells, mix well, and finally dilute it to 1:1000 times. Incubate the cells in a carbon dioxide cell culture incubator at 37℃ for 1 h.

c. Add Nigericin to each well to a final concentration of 10 μg/mL and incubate the cells in a 37 ℃ carbon dioxide cell culture incubator for 30 min.

d. Transfer the culture medium in the wells to a new culture plate, then centrifuge at 3000 rpm for 5 min, and transfer the supernatant to a new 96-well plate.

e. The collected cell culture supernatant samples were tested for human IL-1β content using a commercial ELISA test kit according to the instructions.

The test results are shown in Table 2 below:

Table 2 Inhibitory activity of the compounds of the present invention on NLRP3 in THP-1 cells Test object _IC50 (nM) Compound 23 2.4 Compound 25 2.2 Compound 27 5.2 Compound 33 11.5 Compound 35 3.3 Compound 36 12.7 Compound 37 0.8 Compound 39 0.3 Compound 40 12.8 Compound 41 0.3 Compound 42 4.6 Compound 44 3.6 Compound 45 0.7 Compound 61 1.4 Compound 81 1.1 Compound 82 1.1 Compound 83 6.1 Compound 84 0.2 Compound 85 0.6 Compound 86 0.3 Compound 87 0.7 Compound 88 1.2 Compound 89 0.2 Compound 90 0.4 Compound 91 0.2 Compound 92 0.5 Compound 93 1.4 Compound 94 0.3 Compound 95 0.4 Compound 96 0.5 Compound 97 1.0 Compound 98 5.0 Compound 99 0.7 Compound 100 2.4 Compound 103 0.6 Compound 109 16.0 Compound 111 1.1 Compound 112 12.0 Compound 114 1.3 Compound 115 0.3 Compound 139 1.1 Compound 149 0.5 Compound 161 9.9 Compound 163 1.1 Compound 240 1.3

As can be seen from the experimental results in Table 2, the compounds of the present invention have good inhibitory activity on NLRP3 inflammasome, and therefore the compounds of the present invention can be used to prevent and/or treat diseases associated with NLRP3 inflammasome.

Experimental example 2 ：Evaluation of the liver microsomal stability of the compounds of the present invention

Test substances: the compounds of the present invention and the control substances, prepared according to the method of the embodiment, wherein the control substance is Example Ex 047 in Novartis WO2020234715A1 patent, having the structure

Composition of the experimental incubation system: Substances to be added Initial concentration The proportion Final concentration Phosphate buffer (containing MgCl ₂ ) _K2HPO4 50 mM 67.5% 50 mM _KH2PO4 MgCl ₂ 3 mM 3 mM Liver microsomes 20 mg protein/mL 2.50% 0.5 mg protein/mL Test substance 10 μM 10.0% 1 μM β-NADPH 5 mM 20.0% 1 mM

Test material preparation:

Accurately weigh the appropriate amount of compound and dissolve it in DMSO to prepare a 10.0 mM stock solution. Dilute the 10.0 mM stock solution to 1.0 mM with DMSO, and finally dilute it with phosphate buffer (containing 3 mM MgCl ₂ ) to a 10 μM test substance working solution for later use (DMSO content in the reaction system is 0.1%).

β-NADPH Preparation:

Accurately weigh an appropriate amount of β-NADPH and prepare a 5 mM β-NADPH working solution with phosphate buffer (containing 3 mM MgCl ₂ ) for later use.

Test steps:

(1) Take out liver microsomes (20 mg protein/mL) from the -80℃ freezer, place them in a 37℃ water bath on an oscillator for 3 min, and thaw them for later use.

(2) Prepare the incubation system mixture solution (without compound and β-NADPH) according to the proportions in the “Composition of the experimental incubation system” above, and pre-incubate it in a 37°C water bath on a constant temperature oscillator for 2 min.

(3) Control group (without β-NADPH): Take 10 μL of phosphate buffer (containing 3 mM MgCl ₂ ) and 40 μL of the incubation system mixture in step (2), vortex for 30 seconds, mix well, and the total reaction volume is 50 μL. Cover the wells. Place in a 37°C water bath with a constant temperature oscillator for incubation and start timing. The end time points are 0 min and 60 min.

(4) Sample group: Take 10 μL of β-NADPH solution (5 mM) and 40 μL of the mixed solution described in step (2) respectively, the total reaction volume is 50 μL, vortex for 30 seconds, mix well, cover the wells. Place in a 37℃ water bath constant temperature oscillator for incubation, and start timing. The end time points are 0 min, 5 min, 10 min, 20 min, 30 min, and 60 min.

(5). Vortex for 5 min, then centrifuge at 4000 rpm for 10 min.

(6) Take 50 μL of the supernatant and add 150 μL of water, vortex mix, and analyze by LC/MS/MS.

Data Analysis:

The half-life (t _1/2 ) and clearance (CL) were calculated using the following first-order kinetic formula:

_Ct = _C0 *e ^-kt

t _1/2 = ln 2/k = 0.693/k

Clint = Vd * k

Vd = 1/protein content in liver microsomes

Note: k is the slope of the plot of the logarithm of the residual amount of the compound against time, and Vd is the apparent distribution volume.

The test results are shown in Table 3 below:

Table 3 Stability test of compounds in dog and rat liver microsomes Compound dog Rat Clint (mL/min/mg) t _1/2 (min) Clint (mL/min/mg) t _1/2 (min) Control 0.0296 46.8 0.0420 33.0 twenty three →0 →∞ →0 →∞ 27 →0 →∞ 0.0062 224 42 0.0012 1155 0.0042 330 81 0.0050 277 0.0030 462 82 0.0080 173 0.0104 133 83 0.0038 365 0.0100 139 93 0.0050 277 0.0056 248 100 0.0028 495 0.0084 165 45 0.0014 990 0.0068 204 85 0.0052 267 0.0046 301 99 0.0066 210 0.0032 433 88 0.0016 866 0.0020 693 86 0.0066 210 0.0078 178 84 0.0040 347 0.0040 347 89 0.0062 224 0.0080 173 103 0.0084 165 0.0082 169 149 →0 →∞ →0 →∞ 115 0.0036 385 0.0202 68.6 114 0.0010 1386 0.0004 3465

From the experimental results in Table 3, it can be seen that the compound of the present invention has a lower clearance rate and a longer half-life, and especially compared with the control, the compound of the present invention has excellent metabolic stability.

Experimental example 3 ：Pharmacokinetic study of compounds in mice

Test substances: Compounds of the present invention and control substances, prepared according to the method of the embodiment

Animal medication and sample collection:

A solution was prepared with a mixed solvent consisting of 5% dimethyl sulfoxide, 20% of 30% solutol and 75% saline. The solution of the compound was gavaged into C57BL/6J female mice at a dose of 10 mg/kg, and blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h.

A solution was prepared with a mixed solvent consisting of 5% dimethyl sulfoxide, 20% of 30% solutol and 75% saline. The solution of the compound was administered to C57BL/6J female mice by intravenous bolus at a dose of 5 mg/kg. Blood was collected at the following times: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h.

Sample analysis method:

Take out the sample from the -80℃ freezer, thaw naturally at room temperature, and vortex for 5 min;

Accurately pipette 10 μL plasma samples from different individuals into 1.5 mL centrifuge tubes;

Add 900 μL of 100 ng/mL internal standard working solution (toluamide in acetonitrile) and mix well;

After vortexing for 5 min, centrifuge at 12000 rpm for 5 min;

Accurately pipette 50 μL of supernatant into a 96-well plate pre-filled with 150 μL of water per well;

The mixture was vortexed for 5 min and analyzed by LC-MS/MS.

Data processing method:

The test substance concentration was output using AB's Analyst 1.6.3. Microsoft Excel was used to calculate the mean, standard deviation, coefficient of variation and other parameters (no calculation was required for those directly output by Analyst 1.6.3), and WinNonlin Phenoix 8.2 software NCA was used to calculate the PK parameters (T _max was the median).

result

Table 4 Pharmacokinetic test results of the compounds in mice Compound Dose iv/po (mg/kg) t _z1/2 iv/po (h) V _ss iv (L/kg) Cl _{_obs} iv (L/h/kg) T _max po (h) C _max po (ng/mL) AUC _last iv/po (h*ng/mL) F% Control 5/10 1.18/1.08 5.03 3.30 0.500 1480 1505/3003 99.8 twenty three 5/10 0.920/0.983 1.65 1.54 0.500 3030 3233/5532 85.7 27 5/10 9.55/3.99 2.39 0.708 0.250 5520 6827/10949 77.7 44 5/10 3.95/4.05 2.76 0.551 0.500 1710 8963/12358 69.1 100 5/10 1.65/3.63 2.41 1.08 0.250 1720 4459/6278 68.4 45 5/10 3.57/3.18 1.47 0.436 1.00 4130 11398/19087 83.7 90 5/10 3.23/3.33 6.23 1.24 2.00 900 4018/7579 94.5 85 5/10 5.55/4.26 1.85 0.319 1.00 3540 15132/29105 94.4 84 5/10 3.81/3.10 3.02 0.889 0.500 1910 5589/10398 92.7

Note: t _z1/2 : terminal elimination half-life, Cl _{_obs} : clearance rate, V _ss : volume of distribution, T _max : time to peak blood concentration, C _max : peak concentration, AUC _last : area under the drug-time curve 0-24 h, F%: absolute bioavailability

From the experimental results in Table 4, it can be seen that the compound of the present invention has good pharmacokinetic properties in mice, has a high exposure and oral bioavailability, and in particular, compared with the control, the compound of the present invention has better PK properties in mice.

Experimental example 4 ：Compounds in males SD Pharmacokinetic study in rats

Test substances: Compounds of the present invention and control substances, prepared according to the method of the embodiment

Animal medication and sample collection:

A solution was prepared with a mixed solvent of 5% dimethyl sulfoxide, 20% of 30% solutol and 75% saline. The solution of the compound was gavaged into SD male rats at a dose of 5.0 mg/kg, and blood was collected at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h.

A solution was prepared with a mixed solvent of 5% dimethyl sulfoxide, 20% of 30% solutol and 75% saline. The solution of the compound was administered to SD male rats by intravenous push at a dose of 1.0 mg/kg, and blood was collected at the following times: 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h.

Animals were cannulated through the cervical vein one day before drug administration. About 300 μL of blood was collected through the cervical vein after drug administration. The blood was placed in an anticoagulant tube containing EDTA-K _2. The blood sample was centrifuged at 5000 rpm for 10 min at 4°C to obtain a plasma sample. The plasma was prepared within 30 minutes after blood collection. The plasma was stored in a -80°C refrigerator before testing.

Sample analysis and data processing methods:

Using the same sample analysis method and data processing method as in Experimental Example 3, the following results were obtained:

Table 5 Pharmacokinetic test results of the compounds in SD rats Compound Dose iv/po (mg/kg) t _z1/2 iv/po (h) V _ss iv (L/kg) Cl _{_obs} iv (L/h/kg) T _max po (h) C _max po (ng/mL) AUC _last iv/po (h*ng/mL) F% Control 1/NA 0.707/NA 12.6 13.1 NA NA 66.4/NA NA twenty three 1/5 3.24/3.54 2.15 0.477 0.500 1263 1863/8476 81.0 42 1/5 1.55/3.99 0.694 0.399 1.00 2490 2490/9724 77.8 45 1/5 5.63/5.19 3.28 0.503 4.00 629 1920/6844 71.5

Note: t _z1/2 : terminal elimination half-life, Cl _{_obs} : clearance rate, V _ss : volume of distribution, T _max : time to peak blood concentration, C _max : peak concentration, AUC _last : area under the drug-time curve 0-24 h, F%: absolute bioavailability; NA: not tested or not calculated

From the experimental results in Table 5, it can be seen that the compound of the present invention has a good exposure and oral bioavailability in rats. Compared with the control, the PK properties of the compound of the present invention in rats are better.

Experimental example 5 ：Compounds hERG Potassium channel inhibition assay

Experimental methods

1. Cell culture

1.1 HEK-293 cells with stable expression of hERG potassium channel were cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at 37°C and 5% carbon dioxide concentration. The cell density must not exceed 80%.

1.2 Before the patch clamp assay, cells were separated using TrypLE™ Express and 4×10 ³ cells were plated on a cover slip. After 18 hours, the assay was performed.

2. Preparation method of drug preparation solution

2.1 Blank control: DMSO stock solution.

2.2 Positive control: Weigh an appropriate amount of Cisapride and prepare a 10 mM stock solution with dimethyl sulfoxide (DMSO). Store at -20°C after aliquoting.

2.3 Compounds: Weigh the appropriate mass of the compound, calculate the required volume of DMSO according to the formula: DMSO volume = actual mass × purity (content) / (molecular weight × theoretical concentration), absorb the corresponding volume of DMSO, then dissolve the weighed compound with the absorbed DMSO, weigh the mass of DMSO at the same time, and calculate the actual stock solution concentration based on the final amount of DMSO used.

3. Preparation method of drug preparation working solution

Before the hERG channel current test, dilute the blank control stock solution into an appropriate amount of extracellular fluid as the working solution. Dilute the positive control stock solution and compound stock solution into an appropriate amount of extracellular fluid as the working solution.

The highest test concentration of the compound is obtained by directly diluting the stock solution concentration with the extracellular solution or further diluting the stock solution with DMSO. Other concentrations are first diluted with DMSO from high concentration to low concentration into dilution solutions, and then the dilution solutions are diluted with extracellular solution to the working solution concentration. The concentration of DMSO in each working solution is 0.3%. The compound working solution is ultrasonicated for 20 minutes before the patch clamp test.

4. Concentration selection basis

The default concentrations of the compounds tested were 30, 10, 3, 1, and 0.3 µM. The blank was 0.3% DMSO.

5. Electrophysiological Recording

5.1 Record the liquids used

5.1.1 Extracellular fluid: K-007-1

140 mM NaCl, 3.5 mM KCl, 1 mM MgCl ₂ •6H ₂ O, 2 mM CaCl ₂ •2H ₂ O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH ₂ PO ₄ •2H ₂ O, pH = 7.4 adjusted with NaOH.

5.1.2 Intracellular fluid: K-002-2

20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl ₂ •6H ₂ O, 5 mM EGTA, 10 mM HEPES, 2 mM Na ₂ -ATP, pH = 7.2 adjusted by KOH.

5.2 Diaphragm clamp inspection

The voltage stimulation scheme for recording hERG current by whole-cell patch clamp is as follows: After the whole-cell seal is formed, the cell membrane voltage is clamped at -80 mV. The clamp voltage is depolarized from -80 mV to -50 mV for 0.5 s (as a leakage current detection), then stepped to 30 mV for 2.5 s, and then quickly restored to -50 mV for 4 s to stimulate the tail current of the hERG channel. Data collection is repeated every 10 s to observe the effect of the compound on the hERG tail current. A 0.5 s stimulation of -50 mV is used as a leakage current detection.

Use a microelectrode puller to pull a capillary glass tube into a recording electrode. Install the electrode filled with intracellular fluid into the electrode head, manipulate the microelectrode manipulator under an inverted microscope to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). Contact the electrode to the cell surface, apply negative pressure to form a high-resistance seal (GΩ). At this time, perform fast capacitance compensation, and then continue to apply negative pressure to break the cell membrane and form a whole-cell recording mode. Then perform slow capacitance compensation and record experimental parameters such as membrane capacitance (Cm) and series resistance (Rs). No leakage compensation is given.

When the hERG current recorded by the whole cell is stable, the drug administration begins. After each compound concentration acts for 5 minutes (or the current becomes stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound flow through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during the recording. The current detected by each cell in the external solution without the compound serves as its own control group. At least three cells are used for each concentration and the detection is repeated three times independently. All electrophysiological experiments are performed at room temperature.

6. Data Analysis

_IC50 calculation and curve fitting were performed using GraphPad Prism software.

7. Test Results

Table 6 IC ₅₀ values of the compounds of the present invention on hERG potassium channel Compound hERG IC ₅₀ (μM) Compound 23 >10 Compound 81 >10 Compound 103 >10

From the experimental results in Table 6, it can be seen that the compounds of the present invention have no significant inhibitory effect on hERG potassium ion channels and have good safety.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims (19)

A compound represented by general formula (A') or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof: (A') Where W is selected from , , or ; is selected from a single bond or a double bond; R ₁ is independently selected from hydrogen, hydroxyl, amine, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl or is absent; R ₂ is independently selected from hydrogen, hydroxyl, amine, carboxyl, cyano, nitro, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C R ₁ and R ₂ are each optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C 1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, -N(C _1-6 alkyl) ₂ , -SC 1-6 alkyl or absent; R 1 and R 2 are each optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C 1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; or R ₁ and R ₂ and the C or N atom to which they are connected form a 5-12 membered ring A; the 5-12 membered ring A is optionally substituted by 1-4 groups selected from hydroxyl, amine, carboxyl, cyano, nitro, halogen, carbonyl, oxo, C _1-6 alkyl, -NH-C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylsulfonyl, -N(C _1-6 alkyl) ₂ -membered substituent; the 5-12-membered ring is selected from 5-12-membered cycloalkyl, 5-7-membered cycloalkyl, 5-12-membered cycloalkenyl, 5-7-membered cycloalkenyl, 6-12-membered fused cycloalkyl, 5-12-membered heterocyclic group, 5-7-membered heterocyclic group, 6-12-membered fused heterocyclic group, aryl, 5-12-membered heteroaryl, 8-12-membered fused heteroaryl, 5-7-membered heteroaryl; R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -COR ₅ , -(C _1-6 alkylene) _0-2 -CO-NR ₄ -R ₅ , -(C _1-6 alkylene) _0-2 -NR ₄ -C _1-6 alkylene-R ₅ ; _R4 is selected from hydrogen or _C1-6 alkyl; _R5 is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl; said _R5 is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, _C1-6 alkyl, halogenated _C1-6 alkyl, _C1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, _C2-6 alkenylcarbonyl, sulfonyl, _C1-6 alkylcarbonyl, ureido _C1-6 alkyl, hydroxyl _C1-6 alkyl, hydrazine, _C1-6 alkylsulfonyl C1-6 alkyl; _{the substituents on R5 are selected from C1-6 alkyl ,} halogenated _C1-6 alkyl, C1-6 wherein Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl; wherein Y is substituted by 1-2 substituents selected from C _2-6 alkenyl, C _{2-6 alkynyl, and may be further substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C 1-6} alkyl, halogenated C 1-6 alkyl, C _1-6 alkylsulfonyl; and Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl; wherein Y is substituted by 1-2 substituents selected from C _2-6 alkenyl, C _2-6 alkynyl, and may be further substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _{1-6 alkylamino, C 1-6 alkylcarbonylamino} , C 1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl; the substituent on Y is selected from C 1-6 alkyl, halogenated C 1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituent is optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl; the substituent on Y is selected from C _1-6 alkyl, halogenated C 1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, sulfonyl, and the substituent is optionally substituted by 1-3 substituents selected from halogen, cyano, amino, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl; the substituent on Y is selected from C wherein _W is _{selected from :} When R ₁ and R ₂ do not form a ring with the C to which they are connected. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , R ₁ is selected from hydrogen, hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, C _2-6 alkenyl, C _2-6 alkynyl, 3-7 membered heterocyclic group, 4-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl; said Y is substituted by C _2-6 alkynyl, and may be further optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl; the substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C 1-6 The substituents on Y are selected from C _2-6 alkynyl, and the substituents are optionally substituted with 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 membered cycloalkyl, and halogenated C _1-6 alkyl; R ₅ is optionally substituted with _a substituent selected from hydroxyl C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, hydrazino, _and ureido C _1-6 alkyl. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl; said Y is substituted by C _2-6 alkenyl, and may be further optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl; the substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C 1-6 The substituents on Y are selected from C _2-6 alkenyl, and the substituents are optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, 3-6 cycloalkyl, and halogenated C _1-6 alkyl; R 5 is selected from 3-7 heterocyclic groups, 5-7 cycloalkyl, aryl, 5-7 heteroaryl; the R ₅ is optionally substituted by 1-4 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _2-6 alkyl, 3-6 cycloalkyl, and halogenated C _{2-6 alkyl} ; The group may be substituted with a substituent selected from the group consisting of C _1-6 alkyl, C _1-6 halogenated alkyl, C _1-6 alkoxy, a 3-7 membered heterocyclic group, a 3-7 membered cycloalkyl, an aryl group, a 5-7 membered heteroaryl group, a C _2-6 alkenylcarbonyl group, a sulfonyl group, a C _1-6 alkylcarbonyl group, an ureidoC _1-6 alkyl group, a hydroxylC _1-6 alkyl group, a hydrazino group, and a C _1-6 alkylsulfonylC _1-6 alkyl group. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , at least one of R ₁ and R ₂ is selected from C _2-6 alkenyl, C _2-6 alkynyl, and cyano; R ₁ and R ₂ are each optionally substituted by 1 to 3 substituents selected from hydroxyl, amino, carboxyl, cyano, nitro, halogen, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, and 5-7 membered heteroaryl. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , _R1 is selected from hydrogen; _R2 is selected from hydrogen. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , Y is selected from aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclic group, 3-12 membered cycloalkyl; said Y is substituted by propynyl, and may be further optionally substituted by 1-2 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, halogenated C _1-6 alkyl, C _1-6 alkoxy, 3-7 membered heterocyclic group, 3-7 membered cycloalkyl, aryl, 5-7 membered heteroaryl, C _1-6 alkylamino, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl, aminocarbonyl, C _1-6 alkylaminocarbonyl, sulfonyl, -N(C _1-6 alkyl) ₂ , -SC _1-6 alkyl; the substituents on Y are selected from C _1-6 alkyl, halogenated C _1-6 alkyl, C 1-6 The substituents on Y are selected from propynyl, and the substituents are optionally substituted by 1-3 substituents selected from halogen, cyano, amine, hydroxyl, carbonyl, C _1-6 alkyl, _3-6 membered cycloalkyl, and halogenated _{C 1-6 alkyl} . _R is selected from 3-7 membered cycloalkyl. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; and R ₅ is substituted with 1-2 substituents selected from deuterium, deuterated C _1-6 alkyl groups, ethyl groups, cyclopropyl groups, halogen groups, and halogenated C _1-6 alkyl groups. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , R ₅ is selected from 3-7 membered heterocyclic groups, 3-7 membered cycloalkyl groups, aryl groups, and 5-7 membered heteroaryl groups; and R ₅ is substituted by 1-2 substituents selected from deuterium, hydroxyl, and C _1-6 alkyl groups. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein Y is selected from aryl; Y is substituted with 1-2 substituents selected from C _2-6 alkenyl, C _2-6 alkynyl, and may be further substituted with 1-2 substituents selected from hydroxyl, halogen, and halogenated C _1-6 alkyl. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from ; When R ₂ is hydrogen, R ₁ is not selected from methyl and cyclopropyl. The compound according to claim 3 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein R ₅ is optionally substituted by a substituent selected from hydroxy C _1-6 alkyl, C _1-6 alkoxy C _1-6 alkyl, but excluding the following compounds, , . The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein W is selected from , R ₁ is independently selected from hydrogen, halogen, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl; R ₃ is selected from -(C _1-6 alkylene) _0-2 -NR ₄ R ₅ ; R ₄ is selected from hydrogen or C _1-6 alkyl; R ₅ is selected from 3-7 membered heterocyclic group, 3-7 membered cycloalkyl; said R ₅ is optionally substituted with 1-4 substituents selected from deuterated C _1-6 alkyl, C _1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, hydroxyl, hydroxyl C _1-6 alkyl; Y is selected from aryl; said Y is substituted with C _2-6 alkynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, C 1-6 alkyl, halogenated C _1-6 alkyl, 3-7 membered cycloalkyl, The C _2-6 alkynyl substituent is optionally substituted by _a substituent selected from halogen, C _1-6 alkyl, 3-6 membered cycloalkyl, halogenated C _1-6 alkyl. The compound according to claim 12 or 13, or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein R ₁ and R ₂ are selected from hydrogen, halogen, C _1-6 alkyl, trifluoromethyl, difluoromethyl, cyclopropyl, and cyclobutyl; R ₃ is selected from -NR ₄ R ₅ ; R ₄ is selected from hydrogen or methyl; R ₅ is selected from piperidine, cyclohexyl, cyclopentyl, and cyclobutyl; Y is selected from a benzene ring; Y is substituted with a substituent selected from ethynyl and propynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, C _1-6 alkyl, trifluoromethyl, difluoromethyl, and cyclopropyl; and the ethynyl and propynyl substituents are optionally substituted with a substituent selected from halogen, C _1-6 alkyl, cyclopropyl, trifluoromethyl, and difluoromethyl. The compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, wherein R ₁ and R ₂ are selected from methyl, trifluoromethyl, difluoromethyl, and cyclopropyl; R ₃ is selected from -NR ₄ R ₅ ; R ₄ is selected from hydrogen; R ₅ is selected from piperidinyl; Y is selected from a benzene ring; Y is substituted with a substituent selected from ethynyl and propynyl, and may be further optionally substituted with 1-2 substituents selected from hydroxyl, methyl, trifluoromethyl, difluoromethyl, and cyclopropyl; the ethynyl and propynyl substituents are optionally substituted with a substituent selected from fluorine, methyl, cyclopropyl, trifluoromethyl, and difluoromethyl; the substituent on R ₅ is selected from methyl, ethyl, cyclopropyl, fluorine, chlorine, bromine, difluoroethane, and hydroxyethyl. The following compound or its pharmaceutically acceptable salt, stereoisomer, or deuterated product: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . A pharmaceutical composition comprising the compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, and a pharmaceutically acceptable carrier. Use of a compound as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, or a pharmaceutical composition as described in claim 17 in the preparation of a drug for preventing and/or treating a disease associated with NLRP3 inflammasome. Use of a compound as described in any one of claims 1 to 16 or a pharmaceutically acceptable salt, stereoisomer, or deuterated product thereof, or a pharmaceutical composition as described in claim 17 in the preparation of a drug for preventing and/or treating an inflammasome-related disease, an immune disease, an inflammatory disease, an autoimmune disease, or an autoinflammatory disease.